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Lysіаniy, Mykola, Lyudmila Belskaya, Irina Gnіdkova, and Nastya Palamaryova. "ROLE OF CELLS OF INNATE IMMUNITY IN THE DEVELOPMENT OF MALIGNANT TUMORS OF THE BRAIN." Immunology and Allergy: Science and Practice, no. 4 (December 23, 2019): 4–12. http://dx.doi.org/10.37321/immunology.2019.04-01.
Повний текст джерелаАнотація:
This review presents data on changes in the activity of cells of innate and acquired immunity, namely leukocytes, neutrophils, platelets and lymphocytes in various malignant human tumors, including brain tumors. It was shown that against the background of immunosuppression of specific immunity, especially antitumor reactions, which are caused by factors such as prostaglandin E2, TGF-β, indolamine-2,3-dioxigenase (IDO) and interleukin (IL) -10, which leads to a decrease the sensitivity of T cells to proinflammatory signals and the ineffectiveness of the presentation of tumor antigens to immune cells, activation and polarization of innate immunity cells, namely neutrophils, macrophages and platelets, occurs.
Macrophages are important immune cells of the microenvironment in a tumor site that change their phenotype from M1 cells with antitumor activity to M2, which enhance tumor growth. The release of metalloprotheasis from platelet α -granules destroys the components of the extracellular matrix, increases the ability of cancer cells to pass through the endothelial barrier, penetrate the parenchyma and create metastatic tissue damage. Previously, neutrophils were mainly considered as cells of the body’s first line of defense, mainly with antimicrobial functions, but now they are regarded as cells with tumor-stimulating, “protumorogenic” activity, since in many types of cancer an increased level of neutron is determined with a reduced content of lymphocytes in the peripheral blood and this is associated with a poor prognosis of the disease. The review analyzes the hypothesis that there are three subpopulations of neutrophils in cancer: normal high density neutrophils, immature low density neutrophils (G-MDSC) and large mature low density neutrophils. These types of cells have different functions, for example, neutrophils with high density are antitumor, and with low density - cells that can stimulate tumor growth. ]. Neutrophils realize their activity through molecules such as neutrophilic elastase (NE), cathepsin, arginase 1 (ARG1), matrix metalloproteinase-9 (MMP-9). Multidirectional changes in the parts of the immune system depend on the histogenesis and degree of malignancy of the tumors and indicate differentiated use immunotropic drugs in cancer patients, some should suppress the activity of innate immunity cells, others stimulate the acquired immune response.
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Morenkova, A., M. Tikhonova, T. Tyrinova, E. Batorov, A. Sizikov, O. Chumasova, A. Sulutian, V. Koksharova, D. Orlov, and E. Chernykh. "AB0059 CLINICAL SIGNIFICANCE OF CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS IN PATIENTS WITH ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1331.1–1331. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2998.
Повний текст джерелаАнотація:
Background:Myeloid-derived suppressor cells (MDSCs) represent heterogeneous population of immature myeloid cells with immunosuppressive functions. The important role of MDSCs is indicated for cancer, but their role in autoimmune pathology is currently controversial. Considering the clinical heterogeneity of ankylosing spondylitis (AS) and involvement of innate immunity in AS pathophysiology the investigation of the MDSC role in AS is of great interest.Objectives:The aim of our study is to investigate the number of MDSC subsets in AS patients with different clinical manifestations, activity, disease duration, and treatment options and to evaluate the ability of MDSCs to mediate immunosuppressive function in AS patients.Methods:The study included 34 patients with AS. Ankylosing Spondylitis Disease Activity Score (ASDAS) was used to assess disease activity and high activity was determined as ASDAS≥2.1. The frequencies of monocytic (M-MDSC) (HLADR-CD14 +), granulocytic (G-MDSC) (lin-HLADR-CD33+ CD66 +) and early-stage (eMDSC) (lin-HLADR-CD33 + CD66-) MDSCs and biomarkers of MDSCc functional activity including of Arg-1, IDO, PDL1 were determined in the peripheral blood by flow cytometry.Results:We found significant elevation in the frequency of both M-MDSC and G-MDSC in the total group of patients compared to healthy controls (HC) (P=0.00006 and P=0.008 respectively), while eMDSCs did not differ from HC. Analysis of MDSCs populations in patient subgroups showed expansion of G-MDSCs in patients with axial plus peripheral damages (P=0.004), while M-MDSCs were elevated regardless of the presence (P=0.002) or absence (P=0.001) of peripheral manifestations. Moreover, the percentage of M-MDSCs was positively correlated with ASDAS in patients with axial disease only (R=0.8; P=0.03). Patients with low activity of disease demonstrated significant elevation of only M-MDSCs compared with HC (P=0.001). Patients who had high activity of disease had increase in both M-MDSCs and G-MDSCs (P=0.008 and P=0.005 respectively). By comparing the frequency of MDSCs in patient groups with different AS duration we showed increase in percentage of both M-MDSCs and G-MDSCs in patients with relatively short duration of disease (< Me=11.5 years) (P=0.002 and P=0.005 respectively) and elevation in M-MDSCs only in patients with longer AS duration (P=0.0003). Compared with patients receiving conventional therapy (NSAIDs, csDMARDs), patients who received biological agents (TNFα inhibitors) had lower disease activity but despite this showed elevated frequencies of M-MDSCs and PMN-MDSCs, comparable to patients receiving conventional therapy. Of note, M-MDSCs in AS patients had increased expression of PDL-1 and IDO (P=0.04 and P=0.02 respectively) and similar to HC expression of Arg-1. The expression of Arg-1, IDO, PDL1 in patients G-MDSCs did not differ from HC.Conclusion:The data obtained indicate that both M-MDSCs and G-MDSCs are elevated in AS patients. However, the increase of G-MDSCs is associated with peripheral manifestations of AS, high activity, longer duration, and the percentage of M-MDSCs was positively correlated with activity in patients with axial disease only. The unchanged expression of Arg-1, PDL-1 and IDO in G-MDSCs and enhanced expression of PDL-1 and IDO in M-MDSCs suggest MDSCs capacity to mediate immunosuppressive function in AS patients.Disclosure of Interests:None declared
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Boda, Akash R., Casey R. Ager, Kimal Rajapakshe, Spencer T. Lea, and Michael A. Curran. "High-potency synthetic STING agonists rewire myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic cancer." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 163.08. http://dx.doi.org/10.4049/jimmunol.208.supp.163.08.
Повний текст джерелаАнотація:
Abstract Pancreatic ductal adenocarcinoma (PDAC) is clinically unresponsive to immune checkpoint blockade (ICB) immunotherapy. Dense immunosuppressive myeloid stroma (MS) and consequent T cell exclusion from the tumour microenvironment renders PDAC resistant to immune-based therapies. Innate immune activation of the MS via cyclic dinucleotide (CDN) agonists of the STING (Stimulator of Interferon Genes) pathway can trigger T cell infiltration into cold tumours leading to robust anti-tumour immunity. Despite proven therapeutic efficacy in preclinical models, the cellular mechanisms of how CDNs reprogram the suppressive MS to sensitise tumours to ICB is poorly understood. Using multi-omic profiling of MDSCs and M2 Macrophages of human and murine origin, we show that the synthetic STING agonist, IACS-8803, rewires these populations from immunosuppressive to immune-permissive phenotypes in part through inhibition of c-Myc signaling, energy metabolism modulation, and antagonism of cell cycle. Furthermore, dimensionality reduction analyses of multiparameter flow cytometry data and survival studies in a KPC-derived model of PDAC show a proinflammatory remodeling of the MS and an increased T/NK cell infiltration and function by synthetic CDN STING agonists into the tumour that underlies an amplified therapeutic response to ICB. We are the first to report that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization through altering energy metabolism, cell cycle dynamics and c-Myc signalling. This study uncovers molecular and cellular mechanisms by which high-potency STING agonists drive a proinflammatory conversion of the tumour MS to overcome resistance to ICB in an aggressive orthotopic tumour model of PDAC. Supported by grants from PanCan (206100-90-100300-54-00006617-11111)
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Christofides, Anthos, Carol Cao, Qi Wang, Natalia M. Tijaro-Ovalle, Eirini Konstantinidou, Rushil Shah, Chinmay Jani та ін. "Pparα Ablation Suppresses T Cell Responses and Anti-Tumor Immunity By Compromising the Antigen-Presenting Properties of Tumor-Associated Macrophages". Blood 138, Supplement 1 (5 листопада 2021): 438. http://dx.doi.org/10.1182/blood-2021-149071.
Повний текст джерелаАнотація:
Abstract Peroxisome proliferator activated receptors (PPARs) are transcription factors that belong to nuclear hormone superfamily, with three distinct types identified: PPARapha (PPARα), PPARgamma (PPARγ), and PPARbeta/delta (PPARβ/δ). PPARs possess a critical role in the regulation of lipid metabolism, and thus play critical roles in the differentiation and fate of immune cells. PPARα is involved in lipid and carbohydrate metabolism and PPARα agonists, such as fibrates, have been used for the treatment of hypertriglyceridemia and cardiovascular diseases. PPARα has an anti-inflammatory role during infection, and similar to PPARγ, affects the polarization of macrophages. In acute myelogenous leukemia (AML), PPARα mutations correlate with chemoresistance, poor treatment outcomes and unfavorable prognosis. In experimental tumor models, it has been proposed that PPARα agonists might enhance anti-tumor T cell responses during PD-1 blocking immunotherapy. To dissect the mechanistic role of PPARα in tumor immunity, we used mice with global deletion of PPARα and examined tumor growth and profile of the immunological landscape, using various syngeneic tumor models. Significantly larger B16-F10 melanoma and MC-17 fibrosarcoma tumors were observed in PPARα KO mice compared with wild-type control, suggesting that PPARα deletion attenuated the immunological response against cancer. To dissect the role of PPARα in key populations of the innate and adaptive immune system involved in anti-tumor responses, we analyzed the immunological landscape of tumor, tumor draining lymph nodes (TDLN) and spleen, 14-16 days after tumor implantation. Assessment of CD4 + and CD8 + T cells, CD11b +F4/80 + tumor-associated macrophages (TAMs), CD11b +Ly6C hiLy6G - monocytic myeloid derived suppressor cells (M-MDSC), and CD11b +Ly6C loLy6G + polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), by using flow cytometry, showed no quantitative differences between the two experimental groups. Functionally, MDSC from PPARα KO and WT mice showed comparable immunosuppressive properties as determined by suppression assay using splenocytes from OTI transgenic mice. However, PPARα KO TAMs demonstrated a less activated state, as determined by the lower expression levels of MHC-II that is critical for antigen presentation, and CD86 that is critical for T cell costimulation and prevention of T cell anergy and exhaustion. In agreement with these properties of TAMs, CD4 + T cells from TDLN of PPARα KO mice had diminished expression of activation markers, including PD-1, PD-L1 and ICOS, and numerically decreased central memory-like CD4 + T cells (T CM), compared to control tumor bearing mice. Furthermore, CD69, an emerging marker of T cell exhaustion, was significantly upregulated in CD4 + and CD8 + T cells from the TDLN of PPARα KO mice. To determine whether PPARα ablation altered the cell intrinsic properties of myeloid cells and/or T cells resulting in impaired anti-tumor function, we examined in vitro responses of isolated populations. In response to activation via TCR/CD3 and CD28, PPARα deficient T cells had no significant differences in expansion and cytokine production compared to control. In contrast, PPARα deficient Ly6C + monocytes isolated from the bone marrow displayed diminished responses to TLR-mediated signaling as determined by production of IL-6 and TNFα. Our in vitro and in vivo findings reveal a dominant role of PPARα in regulating the fate of innate immune cells thereby altering T cell responses and anti-tumor function. Our findings have implications for the development of new therapeutic approaches to enhance innate immune cell function for the improvement of cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.
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Nguyen-Pham, Thanh-Nhan, Huong Thi Thanh Tran, Sung-Hoon Jung, Jae-Sook Ahn, Deok-Hwan Yang, Tai Ju Hwang, Hyeoung-Joon Kim, and Je-Jung Lee. "Potent Immunomodulatory Drug Lenalidomide Synergistically Enhance the Effect of Dendritic Cell Vaccination on Multiple Myeloma in Mouse Model,." Blood 118, no. 21 (November 18, 2011): 3237. http://dx.doi.org/10.1182/blood.v118.21.3237.3237.
Повний текст джерелаАнотація:
Abstract Abstract 3237 Introduction: Lenalidomide augment both the adaptive and innate immune system via the co-stimulation of T cells and augmentation of NK and NKT cells, and also can inhibit the frequency and function of suppressor cell. Therefore, lenalidomide could be used to enhance immune response against cancer. Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic modality to treat multiple myeloma (MM). The purpose of this study was to investigate the immunomodulatory effects of lenalidomide in combination with dendritic cells vaccine to treat MM in vivo mouse model. Methods: We used the MOPC315 myeloma murine model to generate tumor-specific CTLs responses by a DC vaccine in combination with lenalidomide. MOPC315 cells were injected subcutaneously into the right flank of 6 to 8-week old mice. After tumor growth, lenalidomide (50 mg/kg/day) were injected intraperitoneal at a three consecutive days to cover the DCs vaccination at day 8, 12, 16, 20. The tumor growth inhibition effect was evaluated to reveal the synergistic effect of DCs and lenalidomide. Using cytotoxic assay, we identified the antitumor effect of splenocytes from vaccinated mice and secretion of IFN-g or IL-10 in response to tumor antigens. The frequency of CD4+, CD8+, NK cells, Gr1+CD11b+ MDSCs, and regulatory T cells in spleens of vaccinated mice were also examined. We then examined the anti-angiogenesis of lenalidomide by measuring the levels of VEGF and TNF-a on tumor tissues of vaccinated mice. Results: The combination of lenalidomide and DCs vaccine efficiently inhibited tumor growth in mouse myeloma model when compared to single therapeutic agent. The cytotoxic assay revealed that the antitumor effects of DCs plus lenalidomide in vaccinated mice were from not only CTLs but also NK cells, respectively. These vaccinated mice exhibit the reduction of suppressor cells including MDSC and regulatory T cell in spleens. In contrast, the reduction of MDSC and regulatory T cells resulted in the increasing proportion of CD4+ and CD8+ T cell in the spleen, and the production of Th1 cytokines (IFN-g) rather than Th2 cytokines (IL-10) in response to tumor antigens. Lenalidomide also enhance the innate immune response by modulating NK cell number and function. In addition, the treatment of lenalidomide can reduce the production of angiogenesis inducing factors including TNF-a and VEGF in tumor-bearing mice. Furthermore, vaccination with DCs plus lenalidomide also inhibited tumor growth in the mice that challenged with MOPC cells compared to control. Conclusions: These results suggest that a treatment combining the immunomodulatory drug lenalidomide with a DC vaccine can improve antitumor immunity in a mouse cancer model by inhibiting immunosuppressor cells and recovering effector cells, as well as superior polarization of the Th1/Th2 balance in favor of Th1. Disclosures: No relevant conflicts of interest to declare.
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Snetsinger, Brooke, Caroline Lin, Willy Weng, Alyssa Cull, Kate Sponagle, Christine Hough, David Lillicrap, and Michael J. Rauh. "Myeloid-Derived Suppressor Cell (MDSC) Dynamics In FVIII-Exposed Hemophilia A Mice: Novel Therapeutic Implications." Blood 122, no. 21 (November 15, 2013): 3569. http://dx.doi.org/10.1182/blood.v122.21.3569.3569.
Повний текст джерелаАнотація:
Abstract Introduction Among FVIII-treated hemophilia A (HA) patients, 25-30% develop FVIII antibodies that inhibit its pro-coagulant function. However, the etiology of FVIII inhibitor formation remains poorly understood, particularly the role played by myeloid innate immune cells. Myeloid-derived suppressor cells (MDSC – CD11b/Gr1 co-expressing, immunosuppressive myeloid cells found in peripheral blood, lymphoid tissue and bone marrow) are expanded in cancer and inhibit adaptive immune responses against tumors. MDSC also mediate organ transplant tolerance. Therefore, we investigated MDSC dynamics during the course of FVIII exposure in HA mice and the potential to harness MDSC as a novel means of mediating FVIII tolerance. Methods 6 to 12 week-old F8-knockout Balb/c hemophilia A mice (HA mice) were used in accordance with Queen's University Animal Care Committee protocols. Over 3 independent experiments, HA mice were either untreated (Week 0; n = 4-6) or tail vein infused weekly for 2 or 4 weeks with 2 IU rhFVIII (Kogenate-FS for 2 experiments or Advate for one; n = 6 and 7, at 2 and 4 weeks) or 200 μl HBSS vehicle alone (n = 4 and 5). Alternatively HA mice were infused weekly with 2 pdFVIII (Wilate) for 2 (n = 2) or 4 weeks (n = 2) or subjected to a 4-day G-CSF preconditioning regimen during Week minus-1 (10 μg/day, SC, in 200 μl HBSS; n = 4) or HBSS alone (n = 4), followed by 2 or 4 weekly rFVIII infusions. Red cell-lysed blood, spleen and bone marrow suspensions were subjected to MDSC flow cytometry using anti-CD11b(Mac1)-APC and anti-Gr1-PE (Miltenyi Biotec). Week 2 and 4 plasma was subjected to anti-FVIII antibody ELISA and Bethesda assays. Means were compared using student's t-test. Results HA mice contained CD11b+Gr1+ MDSC in expected proportions in the blood, bone marrow and spleen. Peripheral blood MDSC proportions declined significantly from baseline following 4 weeks of rFVIII infusions (baseline mean 12.6%, versus 5.9% at 4 weeks, p = 0.041) (Figure 1A). More striking, however, was the observation of diminishing CD11b expression within all three MDSC compartments during the course of rFVIII exposure (magnitude of reduction: 46-65%; at 4 weeks in blood, p = 0.0011; at 2 and 4 weeks in bone marrow, p = 0.0014 and 0.0002; spleen, p = 0.057 and<0.0001) (Figure 1B). To our knowledge, diminished CD11b expression by MDSC has not been previously reported. Suggesting functional significance, 20-40% higher CD11b expression by week 4 MDSC in pdFVIII(Wilate)-treated HA mice (n = 2) was associated with 5 to 30-fold lower Bethesda unit inhibitors as compared to rFVIII. Further in vivo and in vitro studies are underway to confirm the functional impact of diminished MDSC CD11b expression. Next, in anticipation of future adoptive transfer experiments, we asked whether MDSC could be expanded in vitro from the BM of FVIII-na•ve HA mice. Using established 4-day MDSC culture conditions (GM-CSF + IL-6, Marigo et al., Immunity, 2010; or GM-CSF + G-CSF + day-3 IL-13, Highfill et al., Blood, 2010) we were able to achieve 7- to 10-fold expansion of MDSC over standard BM culture. Finally, in anticipation of future expansion of endogenous HA MDSC, we pre-treated a subset of mice with G-CSF (known to expand MDSC in vivo) (n = 4) versus HBSS vehicle (n = 4), followed by weekly rFVIII infusions. Encouragingly, we observed 2- to 4-fold reduced anti-FVIII antibody titres and functional inhibitors in G-CSF-pre-treated mice. G-CSF expansion of MDSC was modest and we are currently optimizing endogenous MDSC expansion regimens. Conclusions For the first time, to our knowledge, we assessed the dynamics of endogenous MDSC in FVIII-treated HA mice, revealing decreased circulating MDSC after 4 weeks of rFVIII exposure, and diminished CD11b expression in all examined MDSC compartments. We hypothesize this phenomenon leads to impaired MDSC function, necessary to mount an optimal adaptive immune response to FVIII, although this awaits further confirmation. Finally, our studies suggest it is feasible to expand MDSC ex vivo from na•ve HA bone marrow for future adoptive transfer experiments, and to expand endogenous HA MDSC using growth factors such as G-CSF, as novel investigative approaches to mediating FVIII tolerance. If warranted by murine studies, G-CSF may be an attractive novel immune tolerance strategy, given extensive clinical experience with human G-CSF administration. Disclosures: No relevant conflicts of interest to declare.
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Boda, Akash, Casey Ager, Kimal Rajapakshe, Spencer Lea, Maria Emilia Di Francesco, Philip Jones, and Michael Curran. "758 High-potency synthetic STING agonists rewire the myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic ductal adenocarcinoma." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A793. http://dx.doi.org/10.1136/jitc-2021-sitc2021.758.
Повний текст джерелаАнотація:
BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is clinically unresponsive to immune checkpoint blockade (ICB) immunotherapy.1 2 High densities of immunosuppressive myeloid cells,3 a paucity of antigen-presenting cells4–6 and T cell exclusion from tumour microenvironment7 all contribute to the refractory nature of PDAC to immune-based therapies. We and others have shown that innate immune activation of myeloid stroma via engagement of the STING (Stimulator of Interferon Genes) pathway can mediate proinflammatory remodeling and trigger a flood of T cell infiltration into otherwise 'cold' tumours.8–11 To that end, intratumoral injection of cyclic dinucleotide (CDN) agonists of the STING pathway has been shown to foster local and abscopal tumor immunity.8–10 Despite proven therapeutic efficacy in preclinical models, the mechanistic basis at a cellular level of how CDNs reprogram the suppressive myeloid stroma to sensitise tumours to ICB is poorly understood.MethodsUsing RNA sequencing and protein arrays we profiled myeloid-derived suppressor cell (MDSC) and M2 macrophage function following stimulation with CDNs of ascending potency. We describe the effects of CDN STING agonists on cell cycle dynamics, metabolic reprogramming and c-Myc expression in MDSCs. Next, in an orthotopic Kras+/G12DTP53+/R172HPdx1-Cre (KPC)-derived model of PDAC, we determined the ability of intratumorally-administered CDNs to sensitise PDAC to checkpoint blockade using bioluminescent in vivo imaging and multi-parameter flow cytometry of tumor stroma post-therapy.ResultsMulti-omics profiling of MDSCs and M2 Macrophages of human and murine origin show that high-potency synthetic STING agonists rewire these populations from immunosuppressive to immune-permissive phenotypes in part through inhibition of c-Myc signaling, energy metabolic modulation, and antagonism of cell cycle. Intratumoral injection of the STING agonist, IACS-8803 resulted in an amplified therapeutic response to checkpoint blockade that was dependent on T/NK cell infiltration into the tumour. Furthermore, dimensionality reduction analyses of multiparameter flow cytometry data show proinflammatory remodeling of the myeloid stroma and enhanced T cell function as salient features of synthetic agonists versus natural CDNs in orchestrating the in vivo therapeutic benefit.ConclusionsThis study uncovers molecular and cellular mechanisms by which STING agonists drive proinflammatory conversion of tumour myeloid stroma. We are the first to report that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization through altering energy metabolism and c-Myc signalling. Lastly, we demonstrate the potential for high-potency STING agonists to overcome resistance to checkpoint blockade in an aggressive orthotopic tumour model of PDAC.ReferencesRoyal RE, Levy C, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33(8):828–33.Brahmer JR, Tykodi SS, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455–65.Karakhanova S, Link J. Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells. Oncoimmunology 2015;4:e998519.Dallal RM, Christakos P, et al. Paucity of dendritic cells in pancreatic cancer. Surgery 2002;131:135–138.Yamamoto T, Yanagimoto H, et al. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J Surg Res 2012;173:299–308.Hegde S, Krisnawan V, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 2020;37(3):289–307.Beatty GL, Winograd R, et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 2015;149(1):201–210.Baird JR, Friedman D, et al. Radiotherapy combined with novel STING-Targeting oligonucleotides results in regression of established tumors. Cancer Res 2016;76(1):50–61.Ager CR, Reilley MJ, et al. Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity. Cancer Immunol Res 2017;5(8):676–84.Smith TT, Moffett HF, et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest 2017;127(6):2176–91.Jing W, McAllister D, et al. STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models. J Immunother Cancer 2019;7(1):115.
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Liang, Hua Laura, Enyu Rao, Yuzhu Hou, Jiaai Wang, Xiaona Huang, Xianbin Yu, Liangliang Wang, Chuan He, Everett Vokes, and Ralph Weichselbaum. "Induction of Inflammatory Macrophages in Solid Tumors by All-trans Retinoic Acid Augments Radiation Efficacy." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 118.06. http://dx.doi.org/10.4049/jimmunol.208.supp.118.06.
Повний текст джерелаАнотація:
Abstract Radiotherapy is an important anticancer treatment modality that activates innate and adaptive immune responses. Local RT induces an influx of myeloid cells (mostly myeloid-derived suppressor cells MDSCs), which suppress T-cell function, in the tumor microenvironment (TME). Alleviating therapy-induced immunosuppression would address a significant barrier to the efficacy of current cancer immunotherapeutic approaches. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared with ionizing radiation (IR) alone or RA alone. The effects of combination treatment were accompanied by a marked increase of tumor necrosis factor–α– (TNFα) and inducible nitric oxide synthase (iNOS)–producing inflammatory macrophages in local and distal nonirradiated tumors. Inflammatory macrophages (Inf-MAC) are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell–derived interferon-γ are crucial for increasing inflammatory macrophage levels in IR- and RA-treated tumors. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR + RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR. Single cell RNAseq of immune infiltrates revealed unique transcriptional changes delineating the differentiation of Inf-Mac in the TME which may lead to potential specific therapeutic targets.
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Lee, Jung-Mi, Min-Ji Chae, Young-Jun Park, Yun-Sun Kim, Eun-Kyung Kim, and Chang-Yuil Kang. "Serum amyloid A3 mediates inflammation-related tumor growth by fortifying the immunosuppressive mechanism of myeloid-derived suppressor cells (162.7)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 162.7. http://dx.doi.org/10.4049/jimmunol.188.supp.162.7.
Повний текст джерелаАнотація:
Abstract Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immunity and thereby provide a tumor evasion mechanism, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors inducing MDSCs have been known, the crucial components and the underline mechanisms remain elusive. In this study, we demonstrated for the first time a novel mechanism of serum amyloid A (SAA) 3, a well-known inflammatory marker, connecting inflammation and MDSCs. We found that tumor progression or hSAA treatment specifically acted on Mo MDSCs in subsets of MDSCs to induce SAA3 expression. These resulted in enhancing the survival and suppressive function while inhibiting the GM-CSF-induced differentiation of Mo MDSCs to activated macrophages through TLR2 signaling. Therefore, it suggests a novel mechanism that inflammation exacerbates cancer progression with the mediation of Mo MDSCs through SAA3. This study also provides new insight into increasing immunosuppressive activity of Mo MDSCs with tumor growth, demonstrating that SAA3 is specifically increased in Mo MDSCs as tumor grows.
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Parker, Katherine, and Suzanne Ostrand-Osenberg. "Title: HMGB1 both enhances and blocks myeloid-derived suppressor cell potency Katherine H. Parker, Suzanne Ostrand-Rosenberg Department of Biological Sciences, University of Maryland Baltimore County, Baltimore MD 21250 (162.40)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 162.40. http://dx.doi.org/10.4049/jimmunol.188.supp.162.40.
Повний текст джерелаАнотація:
Abstract Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in individuals with cancer and inflammation and play a pivotal role in tumor immunity by suppressing T-cell activation and secreting proinflammatory molecules. MDSC potency is mediated by immune suppressive factors such as inducible NO synthase (iNOs), arginase, and reactive oxygen species (ROS). MDSC also impair tumor immunity through crosstalk with macrophages in which IL-10 production increases while IL-12 production decreases, causing a shift in innate and adaptive immunity towards a type 2 tumor-promoting phenotype. Nuclear protein, High Mobility Group Box1 (HMGB1) is the second most abundant protein within a cell and is released from myeloid cells as a danger response to sepsis, infection, or arthritis. It’s release promotes inflammatory responses. HMGB1 signals through a multitude of receptors including TLR4 and RAGE, which are expressed by MDSC. In contrast to other inflammatory mediators which increase MDSC potency, HMGB1 reduced the suppressive mechanisms of TLR4-\- and wildtype MDSC, by reducing ROS in TLR4-\- MDSC and iNOs levels in wildtype MDSC. Glycyrrhizin, an HMGB1 inhibitor, decreased IL-10 in co-cultures of macrophages and MDSC. These findings suggest that HMGB1 plays both anti- and pro-inflammatory roles in regulating MDSC suppressive activity.
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Cimen Bozkus, Cansu, Bennett Elzey, Scott Crist, Lesley Ellies, and Timothy Ratliff. "Expression of cationic amino acid transporter 2 is required for myeloid derived suppressor cell-mediated control of T cell immunity (IRC4P.460)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 57.13. http://dx.doi.org/10.4049/jimmunol.194.supp.57.13.
Повний текст джерелаАнотація:
Abstract Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature cells that expand during benign and cancer-associated inflammation. MDSC regulate innate and adaptive immunity, notably by inhibiting T cell functions. Increased metabolism of L-Arginine (L-Arg), through arginase 1 (ARG1) and nitric oxide synthase 2 (NOS2), is well documented as a major MDSC suppressive mechanism. However, the mechanism by which extracellular L-Arg is transported into MDSC is not defined. Using murine models of prostate specific inflammation and cancer, we show that MDSC recruited to localized inflammation and tumor sites upregulate cationic amino acid transporter 2 (Cat2) coordinately with Arg1 and Nos2. CAT2 contributes to the transport of L-Arg in MDSC and acts as an important regulator of MDSC suppressive function. MDSC that lack CAT2 have significantly reduced suppressive ability ex vivo and display impaired capacity for regulating T cell responses in vivo as evidenced by increased T cell expansion and decreased tumor growth in Cat2-/- mice. The abrogation of suppressive function is due to lower L-Arg uptake, which leads to the impaired ability of NOS2 to catalyze L-Arg metabolic processes. These findings demonstrate that CAT2 is an important regulator of MDSC suppressive function. In the absence of CAT2 MDSC display diminished capacity for controlling T cell immunity in prostate inflammation and cancer models, where the loss of CAT2 results in enhanced antitumor activity.
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Ding, Chuanlin, and Jun Yan. "Chemotherapy-derived inflammatory responses promote the differentiation and immunosuppressive activity of monocytic-MDSC." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 213.1. http://dx.doi.org/10.4049/jimmunol.196.supp.213.1.
Повний текст джерелаАнотація:
Abstract Emerging evidence has unveiled the contribution of tumor microenvironment to the regulation of chemotherapeutic outcomes. However, the impact of chemotherapy on anti-tumor immunity and immunosuppression still remains elusive. In this study, we investigated the role of chemotherapy-derived inflammatory responses in the differentiation of myeloid-derived suppressive cells (MDSC). The anti-cancer agents Gemcitabine and Carboplatin induced the activation of MAPK pathway in mouse mammary cancer cell line EO771 and also stimulated cytokine and chemokine production including GM-CSF and IL-6. The supernatants of Gemcitabine-treated tumor cells promoted more bone marrow-derived monocytic MDSC differentiation, and enhanced their immunosuppressive activity on effector T cells. The expression of MDSC associated molecules such as Arginase and iNOS significantly increased in M-MDSC induced by the supernatant of Gemcitabine-treated tumor cells. In vivo treatment of EO771 tumors with Gemcitabine increased the suppressive function of MDSC. Our findings also suggest that Dectin-1 activation by β-glucan could significantly reduce MDSC suppressive function. Together, these results describe a role of chemotherapy-derived inflammation in the modification of chemotherapy-treated tumor microenvironment and suggest the targeting of Dectin-1 signaling may benefit cancer patients by reprogramming MDSC in chemotherapy setting.
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Waight, Jeremy, and Scott Abrams. "Tumor-derived G-CSF promotes granulocytic MDSC development in vivo (66.34)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 66.34. http://dx.doi.org/10.4049/jimmunol.186.supp.66.34.
Повний текст джерелаАнотація:
Abstract Myeloid-derived suppressor cells (MDSC) comprise a heterogeneous population of myeloid cells with the capacity to suppress tumor immunity. Consequently, these cells represent a significant impediment to effective cancer immunotherapy. While the mechanisms by which these cells mediate immunosuppression is well-established, details on how they develop remain poorly understood. Broadly speaking, it is known that tumor-derived factors play significant roles in diverse aspects of MDSC biology. Given that MDSC accumulation is a result of altered myelopoiesis and that a major subset is granulocytic, we tested the hypothesis that tumor-derived granulocyte-colony stimulating factor (G-CSF) promotes MDSC development. Using both implantable and autochthonous mouse mammary tumor models, we observed abundant amounts of G-CSF in vivo, which correlated with a massive accumulation of granulocytic MDSC. To determine a causal role of G-CSF in MDSC generation, we established both gain- and loss-of-function approaches. First, administration of recombinant G-CSF alone elicited immunosuppressive granulocytic MDSC. Secondly, over-expression of G-CSF in G-CSF-negative tumors led to granulocytic MDSC accumulation. Lastly, inhibiting G-CSF culminated in a significant reduction of granulocytic MDSC. Collectively, our studies demonstrate the importance of tumor-derived G-CSF in MDSC development, thus providing new insights into the identity of putative targets for therapeutic applications.
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Yan, De hong, Jing hui Wang, and Xiao chun Wan. "TIPE2 is a novel direct target of STAT3 in MDSC and inhibition of its expression on MDSC enhanced T cell activation in tumor." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 205.3. http://dx.doi.org/10.4049/jimmunol.198.supp.205.3.
Повний текст джерелаАнотація:
Abstract MDSCs represent an immature population of myeloid cells that inhibit both innate and adaptive immunity in most cancer patients and mice bearing various tumors through several inflammatory mediators. TIPE2, a member of tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) family, is a negative regulator of innate and adaptive immunity. In this study, we investigated the influence of tumor-derived factors on TIPE2 expression in MDSCs. We demonstrate that tumor-derived IL-6 induced TIPE2 up-regulation expression of MDSCs. This effect was dependent on phosphorylation signal transducer of activator of transcription 3 (STAT3) and blockade of STAT3 signaling also reversed the effect of tumor-derived IL-6 on TIPE2 expression in MDSCs. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of STAT3 to a transcriptionally active STAT3-response element (SRE) in the TIPE2 proximal promoter. Inhibition of TIPE2 expression on MDSCs by shRNA technology enhanced T cell activation and abrogated the suppressive activity of MDSCs. More importantly, downregulation of TIPE2 level on MDSCs by stattic, a STAT3 inhibitor, significantly delayed tumor growth in tumor-bearing mice. Targeting of TIPE2 therapy may represent a novel approach for cancer immunotherapy.
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Sinha, Pratima, Olesya Chornoguz, Virginia Clements, Konstantin Artemenko, Roman Zubarev, and Suzanne Ostrand-Rosenberg. "Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL (100.18)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 100.18. http://dx.doi.org/10.4049/jimmunol.184.supp.100.18.
Повний текст джерелаАнотація:
Abstract Myeloid-derived suppressor cells (MDSC) accumulate to high levels in individuals with a variety of conditions including cancer, chronic inflammation, and stress, where they are potent inhibitors of adaptive and innate immunity. Some of the factors that induce their accumulation are known; however, physiological conditions that regulate their turn-over have not been identified. Mass spectrometry analysis revealed prominent expression of apoptosis pathway proteins by MDSC and led us to hypothesize that Fas/FasL-mediated apoptosis may be a key mechanism that regulates MDSC turn-over. This hypothesis was confirmed by the findings that MDSC levels significantly regress after removal of primary mammary tumors from STAT6-deficient or CD-1-deficient mice, but do not regress in mice doubly deficient for FasL and STAT6 or CD-1. Flow cytometry and confocal microscopy studies examining activated caspase 3 expression and cytochrome C localization revealed that MDSC apoptosis is triggered via the extrinsic, and not the intrinsic, pathway. Surprisingly, activated FasL+ T cells mediated MDSC apoptosis in vivo, demonstrating a retaliatory relationship between these two cell populations, and suggesting that Fas-FasL interactions could be exploited as a strategy to reduce in vivo levels of MDSC.
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Bie, Qingli, Pan Zhang, Zhaoliang Su, Dong Zheng, Xinyu Ying, Yumin Wu, Huijian Yang, Deyu Chen, Shengjun Wang, and Huaxi Xu. "Polarization of ILC2s in Peripheral Blood Might Contribute to Immunosuppressive Microenvironment in Patients with Gastric Cancer." Journal of Immunology Research 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/923135.
Повний текст джерелаАнотація:
Newly identified nuocytes or group 2 innate lymphoid cells (ILC2s) play an important role in Th2 cell mediated immunity such as protective immune responses to helminth parasites, allergic asthma, and chronic rhinosinusitis. However, the contributions of ILC2s in the occurrence and development of cancer remain unknown. Our previous study found that there was a predominant Th2 phenotype in patients with gastric cancer. In this study, the ILC2s related genes or molecules in PBMC from patients with gastric cancer were measured, and the potential correlation between them was analyzed. The expression levels of RORα, GATA3, T1/ST2, IL-17RB, CRTH2, IL-33, IL-5, and IL-4 mRNA were significantly increased in patients, but no significant changes were found in ICOS, CD45, and IL-13 expression, and there was a positive correlation between RORαor IL-13 and other related factors, such as ICOS and CD45. The increased frequency of ILC2s was also found in PBMC of patients by flow cytometry. In addition, the mRNA of Arg1 and iNOS were also significantly increased in patients. These results suggested that there are polarized ILC2s in gastric cancer patients which might contribute to immunosuppressive microenvironment and closely related to the upregulation of MDSCs and M2 macrophages.
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Kvell, K., EL Cooper, P. Engelmann, J. Bovari, and P. Nemeth. "Blurring Borders: Innate Immunity with Adaptive Features." Clinical and Developmental Immunology 2007 (2007): 1–10. http://dx.doi.org/10.1155/2007/83671.
Повний текст джерелаАнотація:
Adaptive immunity has often been considered the penultimate of immune capacities. That system is now being deconstructed to encompass less stringent rules that govern its initiation, actual effector activity, and ambivalent results. Expanding the repertoire of innate immunity found in all invertebrates has greatly facilitated the relaxation of convictions concerning what actually constitutes innate and adaptive immunity. Two animal models, incidentally not on the line of chordate evolution (C. elegansandDrosophila), have contributed enormously to defining homology. The characteristics of specificity and memory and whether the antigen is pathogenic or nonpathogenic reveal considerable information on homology, thus deconstructing the more fundamentalist view. Senescence, cancer, and immunosuppression often associated with mammals that possess both innate and adaptive immunity also exist in invertebrates that only possess innate immunity. Strict definitions become blurred casting skepticism on the utility of creating rigid definitions of what innate and adaptive immunity are without considering overlaps.
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Christofides, Anthos, Natalia M. Tijaro-Ovalle, Halil-Ibrahim Aksoylar, Rinku Pal, Abdelrahman AA Mahmoud, Laura Strauss, Nikolaos Patsoukis, and Vassiliki A. Boussiotis. "Myeloid-Specific SHP-2 Ablation Induces Robust Anti-Tumor Immunity That Is Not Further Enhanced By PD-1 Blockade." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-138975.
Повний текст джерелаАнотація:
PD-1 is a T cell inhibitor for which blocking agents have achieved success as anti-cancer therapeutics. The current view is that cancer limits host immune responses by upregulating PD-L1 in the tumor microenvironment thereby causing PD-1 ligation and inactivation of CD8+ Teff cells. Recently, we determined that PD-1 alters the differentiation of myeloid progenitors during cancer-mediated emergency myelopoiesis. We found that PD-1 is expressed in granulocyte/macrophage progenitors (GMP), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSC) that promote tumor growth. In tumor-bearing mice with myeloid-specific PD-1 ablation, accumulation of GMP and MDSC was prevented, while output of effector myeloid cells was increased. PD-1-mediated T cell inactivation is attributed to the function of SHP-2 phosphatase, which is activated by recruitment to PD-1 cytoplasmic tail. Temporal activation of SHP-2 is critical for myeloid cell fate. Activating SHP-2 mutations prevent myeloid cell differentiation and lead to the accumulation of immature myelocytes and development of leukemia. To determine whether PD-1-mediated inhibition of anti-tumor immunity relies on SHP-2-mediated effects in T cells or myeloid cells, we generated mice with conditional targeting of the Ptpn11 gene (encoding for Shp-2) and selectively eliminated Shp-2 in T cells (Shp-2fl/flLckCre) or myeloid cells (Shp-2fl/flLysMCre). No significant difference in tumor growth was observed between control Shp2fl/fl and Shp-2fl/flLckCre mice bearing B16-F10 melanoma. Strikingly, Shp-2fl/flLysMCre mice had significantly diminished tumor growth that was not further decreased by anti-PD-1 antibody, in contrast to control Shp-2fl/fl mice in which anti-PD-1 treatment significantly reduced tumor size. To determine how Shp-2 ablation affected the properties of myeloid cells, we examined CD11b+Ly6ChiLy6G- monocytic (M-MDSC), CD11b+Ly6CloLy6G+ polymorphonuclear (PMN-MDSC), CD11b+F4/80+ tumor-associated macrophages (TAM) and CD11c+MHCII+ dendritic cells (DC). No quantitative differences were observed in these myeloid subsets in tumor bearing mice among the different groups. However, M-MDSC from Shp-2fl/flLysMCre mice had elevated expression of CD86 and IFNγ, consistent with effector differentiation. Suppression assays, by measuring antigen-specific responses of OTI transgenic T cells, showed significantly attenuated suppressor function of MDSC isolated from tumor-bearing Shp-2f/fLysMCre mice compared to control or Shp-2f/fLckCre mice. CD38 is a key mediator of MDSC-mediated immunosuppression. It is an ADP-ribosyl cyclase that has ectoenzyme and receptor functions, is induced early during differentiation of myeloid progenitors by retinoic acid receptor alpha (RARα) signaling, and mediates T cell immunosuppression. Because Shp-2 is involved in the differentiation of myeloid progenitors, we examined CD38 expression. We found that expression of CD38 was significantly reduced in MDSC from Shp-2fl/flLysMCre mice compared to control and Shp-2fl/flLckCre-tumor bearing mice. Since the suppressive potency of MDSC is decreased by autophagy, and SHP-2 has been implicated in regulating autophagy in cancer cells, we examined autophagy of MDSC in our system. Assessment of autophagy in ex vivo isolated MDSC, using Cyto-ID that stains the autophagosome membrane and indicates autophagic activity, showed enhanced autophagy in MDSC isolated from tumor bearing Shp-2fl/flLysMCre mice compared to control or Shp-2fl/flLckCre mice. Enhanced autophagy was also detected in bone marrow-derived MDSC from Shp-2fl/flLysMCre mice as determined by accumulation of LC3B-II and p62 during culture under conditions of starvation-induced stress. Consistent with the diminished MDSC suppressor function, myeloid cell-specific Shp-2 ablation in tumor-bearing mice induced an increase of CD8+ T cells showing an effector phenotype with improved functionality, despite preserved expression of PD-1 and Shp-2. Together these results indicate that inhibition of PD-1-mediated SHP-2 activation in myeloid progenitors, thereby preventing the accumulation of immature immunosuppressive MDSC and promoting the differentiation of effector myeloid cells, might be a previously unidentified mechanism by which PD-1 blockade mediates anti-tumor function. Disclosures No relevant conflicts of interest to declare.
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McGill, Andrew Robert, Tomar Ghansah, Ivannie Ortiz-Rivera, and Cristina Iclozan. "Time-course analysis of SHIP-1 modulation and expression in a pancreatic cancer model." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 211.9. http://dx.doi.org/10.4049/jimmunol.196.supp.211.9.
Повний текст джерелаАнотація:
Abstract Pancreatic cancer (PC) is an aggressive disease with minimally effective therapies due to immunosuppression. Src Homology Inositol Phosphatase (SHIP-1) expression is essential in regulating myeloid derived suppressor cell (MDSC) and T regulatory cell (Treg) homeostasis and function, which can positively or negatively impact antitumor immunity. Inflammatory factors play an important role in the regulation of SHIP-1 expression. We demonstrated in our pancreatic cancer tumor bearing mice (TB) that SHIP-1 gene and protein expression is diminished in lymphoid tissues, correlating with an expansion of MDSC and Treg percentages compared to control mice (CTRL). These TB mice are generated via subcutaneous injection with Panc02 cells. Furthermore, we showed that inflammatory factors were elevated in TB mice compared to CTRL mice. In this study we sought to pinpoint the exact time when SHIP-1 expression was reduced, in correlation with the expansion of MDSC and Treg, along with the increase in production of inflammatory factors in TB mice. To evaluate the loss of SHIP-1, weekly time-course experiments were performed via collection of peripheral blood (PB) and lymphoid tissues for a total of 4 weeks. Preliminary data indicates a reduction of SHIP-1 expression two weeks post tumor inoculation, which correlated with the expansion of MDSC and Treg percentages and an increase in tumor and spleen weights in TB mice compared to CTRL mice. Also, PB from TB mice showed a weekly increase in the production of inflammatory factors compared to CTRL mice. The results from this study may further establish SHIP-1 as a potential therapeutic target that may help combat PC in humans.
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Chaib, Mehdi, Liza Makowski, John Yarbro, Laura Sipe, and Deidre Daria. "682 PKC agonism restricts innate immune suppression, promotes antigen cross-presentation and synergizes with agonistic CD40 therapy in breast cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A710. http://dx.doi.org/10.1136/jitc-2021-sitc2021.682.
Повний текст джерелаАнотація:
BackgroundImmunotherapies that reinvigorate T cell responses have transformed the treatment of many cancers showing unprecedented durable antitumor responses. However, most patients do not respond to immunotherapy due in part to immunosuppression. Immunotherapy non-responders have high levels of circulating myeloid-derived suppressor cells (MDSCs)- an innate cell population that expands in pathological conditions such as cancer and suppresses T cells via production of immunosuppressive factors. In contrast, immunotherapy success is dependent on the ability of antigen-presenting cells (APCs) to cross-present tumor antigens to cytotoxic T cells. Immunogenic cross-presentation by APCs requires a specific subtype of dendritic cells (DCs) called conventional DC1 (cDC1) which are dysfunctional in cancer. Novel ways to increase cDC1 function are promising and under active investigation. One of these ways is ligation of CD40 which is primarily expressed by myeloid cells and its agonism leads to myeloid cell activation. Thus, targeting MDSCs while simultaneously expanding cross-presenting DCs represents a promising strategy that, when combined with agonistic CD40, will likely result in long-lasting protective immunity.MethodsUsing in vitro, ex vivo, in vivo and adoptive transfer systems, we investigated the effect of PKC agonists PEP005 and prostratin on MDSC expansion, differentiation to APC-like cells and recruitment to the TME. MDSC suppressive capacity was investigated using functional coculture assays with CD8+ T cells. Furthermore, we assessed the effect of PKC agonists on MDSC cross-priming capacity using in vitro coculture assay with OT-I CD8+ T cells as well as adoptive transfer experiments. We also investigated the effect of PKC agonists on cDC1 expansion from the BM in vitro and in vivo. Finally, we tested the efficacy of PKC agonism in combination with agonistic CD40 using the E0771 murine breast cancer orthotopic mouse model.ResultsHerein, we show that PKC agonists decreased MDSC expansion from hematopoetic progenitors in the BM and induced M-MDSC differentiation to an APC-like phenotype that expresses cDC1-related markers and the transcription factor Irf8. Simultaneously, PKC agonists favored cDC1 expansion at the expense of cDC2 and plasmocytoid DCs (pDC). Functionally, PKC agonists blunted MDSC suppressive function of T cells and promoted MDSC cross-priming capacity. Finally, combination of PKC agonism with agonistic CD40 mAb resulted in a marked reduction in tumor growth while synergistically increased intratumoral activated CD8+ T cells and tissue-resident memory CD8+ T cells.ConclusionsIn sum, we propose a novel promising strategy to simultaneously target MDSCs and promote APC function that may have potential clinical relevance in cancer patients.
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Petricca, Lydia E., Alexandra R. Witter, Natasha D. Sheybani, Eric A. Thim, Timothy N. Bullock, and Richard J. Price. "Targeting immunosuppression for enhanced focused ultrasound efficacy in triple negative breast cancer." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 117.14. http://dx.doi.org/10.4049/jimmunol.208.supp.117.14.
Повний текст джерелаАнотація:
Abstract Immunologic rejection of triple-negative breast cancer (TNBC) is rare. Focused Ultrasound (FUS) promotes anti-tumor immunity by inducing tissue destruction and inflammation. We hypothesized that thermally-ablative FUS (tFUS) would increase the immune response to TNBC. However, TNBC is commonly accompanied by the expansion of immunosuppressive myeloid cells. By implanting a metastasizing TNBC cell line, 4T1, into BALB/c mice, we showed that a combinatorial therapy of tFUS and Gemcitabine (GEM), a myeloablative chemotherapy, was able to control primary tumor growth and reduce mortality. This response is dependent on T cell-mediated immunity. While this treatment remarkably resulted in some cures, the effects were not durable in every case; suggesting immunosuppression may be re-established. We hypothesize GEM is synergizing with FUS to immunologically control tumor growth by either depleting myeloid derived suppressor cells (MDSCs) or inducing tumor cell death. To discriminate between these possibilities, we will use a Ly6G-specific 1A8 antibody to deplete the MDSC population. In parallel, we are interrogating the ability of GEM to induce immunogenic cell death in this model. Current studies are focused on understanding alterations and the role of CD4 and CD8 T cells in tumor control after FUS+GEM therapy. Finally, RNAseq analysis has been performed on treated samples to develop hypotheses to explain the effectiveness of dual therapy. Notably, similar therapeutic approaches are now ongoing as a clinical trial at our institution. We expect our studies to reveal the mechanistic basis in which FUS and GEM are eliciting an immunological response resulting in primary tumor growth control and an overall survival advantage. Supported by grants from NIH (R01 164985 101 GB10846 41017)
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Smola, Sigrun, Connie Trimble, and Peter L. Stern. "Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy." Therapeutic Advances in Vaccines 5, no. 3 (June 2017): 69–82. http://dx.doi.org/10.1177/2051013617717914.
Повний текст джерелаАнотація:
It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.
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Lee, Hyo Jun, Jiae Koh та Jongsun Kim. "INF-γ production of NK cells is suppressed in cancer patients. (45.10)". Journal of Immunology 188, № 1_Supplement (1 травня 2012): 45.10. http://dx.doi.org/10.4049/jimmunol.188.supp.45.10.
Повний текст джерелаАнотація:
Abstract Natural killer (NK) cells are the innate immune system that play an important role in killing viral infected and transformed cancer cells by direct cell to cell interaction. NK cells also secrete cytokines such as interferon (IFN)-γ and TNF-α which primes subsequent adaptive immune responses. However, tumor cells employ many different strategies to evade NK cells. Moreover, tumor cells secrete molecules to directly inhibit the function of immune cells of both innate and adaptive immunity. Here, we designed to investigate whether NK cells from cancer patients exhibit an altered ability to produce INF-γ. The results showed that peripheral blood mononuclear cells (PBMC) and purified NK cells of the cancer patients had suppressed ability to produce IFN-γ. Therefore, we propose that impaired IFN-γ production in peripheral blood mononuclear cells and in purified NK cells reflects immunosuppression and inadequate antitumor immune response in cancer patients. Thus, the measurement of INF-γ producing ability of NK cells in clinical blood samples may allow to assess the impact of immunosuppression on these effector cells, and this information may be helpful in understanding cancer and pathogenesis.
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Brock, Rebecca Michaela, Natalie Beitel-White, Alissa Danielle Hendricks, Allison Zeher, Navid Manuchehrabadi, Rafael V. Davalos, and Irving C. Allen. "Irreversible electroporation can alter immune cell composition and enhance antigen presentation potential in pancreatic cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.29. http://dx.doi.org/10.4049/jimmunol.204.supp.242.29.
Повний текст джерелаАнотація:
Abstract Pancreatic cancer has a devastating survival rate of only 9%. A major treatment limitation is the immunosuppressive nature of pancreatic tumors created by high amounts of tumor-associate stromal cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). These form a barrier that inhibits anti-tumor immunity and has yet to be overcome by current immunotherapy options. Irreversible electroporation (IRE), an ablative technology that utilizes short electrical pulses to disrupt tumor cell membranes, shows evidence of inducing proinflammatory cell death in pancreatic tumors, but its effect on innate and adaptive immune responses, vital for long-term survival, has not been investigated. We hypothesize that IRE treatment for pancreatic cancer can reduce pro-tumor immune cells, recruit anti-tumor immune cells such as cytotoxic T-cells, and increase tumor-specific antigen presentation potential. We utilized in vivo immunocompetent Pan02 murine pancreatic cancer models to assess progression-free survival and tumor immune cell populations via flow cytometry, as well as an ex vivo antigen presentation model with murine bone marrow-derived dendritic cells and splenic T-cells to determine the ability of IRE to generate viable antigens. Our findings show a temporal increase in anti-tumor immune cell populations, reduction in tumor-associated immune cell populations, and strong antigen presentation potential. However, we also observed an increase in Pdl-1, normally down-regulated in pancreatic cancer, in response to increased immune signaling. This may make IRE a candidate for cotherapy options such as anti-Pdl-1 antibodies or other immunotherapies that could increase patient survival.
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Serafini, Paolo, Kristen Meckel, Michael Kelso, Kimberly Noonan, Joseph Califano, Wayne Koch, Luigi Dolcetti, Vincenzo Bronte, and Ivan Borrello. "Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function." Journal of Experimental Medicine 203, no. 12 (November 13, 2006): 2691–702. http://dx.doi.org/10.1084/jem.20061104.
Повний текст джерелаАнотація:
Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions. We report the use of PDE5 inhibitors as modulators of the antitumor immune response. In several mouse tumor models, PDE5 inhibition reverses tumor-induced immunosuppressive mechanisms and enables a measurable antitumor immune response to be generated that substantially delays tumor progression. In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase–2 expression, thereby reducing the suppressive machinery of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) recruited by growing tumors. By removing these tumor escape mechanisms, sildenafil enhances intratumoral T cell infiltration and activation, reduces tumor outgrowth, and improves the antitumor efficacy of adoptive T cell therapy. Sildenafil also restores in vitro T cell proliferation of peripheral blood mononuclear cells from multiple myeloma and head and neck cancer patients. In light of the recent data that enzymes mediating MDSC-dependent immunosuppression in mice are active also in humans, these findings demonstrate a potentially novel use of PDE5 inhibitors as adjuncts to tumor-specific immune therapy.
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Arkhypov, Ihor, Feyza Gül Özbay Kurt, Rebekka Bitsch, Daniel Novak, Vera Petrova, Samantha Lasser, Thomas Hielscher та ін. "HSP90α induces immunosuppressive myeloid cells in melanoma via TLR4 signaling". Journal for ImmunoTherapy of Cancer 10, № 9 (вересень 2022): e005551. http://dx.doi.org/10.1136/jitc-2022-005551.
Повний текст джерелаАнотація:
BackgroundTumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors. Their interactions with myeloid cells lead to the generation of myeloid-derived suppressor cells (MDSC), which inhibit the antitumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced immunosuppressive activity via increased expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90α (HSP90α) in EV. Here, we investigated whether soluble HSP90α could convert monocytes into MDSC.MethodsCD14 monocytes were isolated from the peripheral blood of healthy donors, incubated with human recombinant HSP90α (rHSP90α) alone or in the presence of inhibitors of TLR4 signaling and analyzed by flow cytometry. Inhibition of T cell proliferation assay was applied to assess the immunosuppressive function of rHSP90α-treated monocytes. HSP90α levels were measured by ELISA in plasma of patients with advanced melanoma and correlated with clinical outcome.ResultsWe found that the incubation of monocytes with rHSP90α resulted in a strong upregulation of PD-L1 expression, whereas reactive oxygen species (ROS) and nitric oxide (NO) production as well as the expression of arginase-1, ectoenzymes CD39 and CD73 remained unchanged. The PD-L1 upregulation was blocked by anti-TLR4 antibodies and a nuclear factor-κB inhibitor. rHSP90α-treated monocytes displayed the downregulation of HLA-DR expression and acquired the resistance to apoptosis. Moreover, these monocytes were converted into MDSC as indicated by their capacity to inhibit T cell proliferation, which was mediated by TLR4 signaling as well as PD-L1 and indoleamine 2,3-dioxygenase (IDO) 1 expression. Higher levels of HSP90α in plasma of patients with melanoma correlated with augmented PD-L1 expression on circulating monocytic (M)-MDSC. Patients with melanoma with high levels of HSP90α displayed shorter progression-free survival (PFS) on the treatment with immune checkpoint inhibitors (ICIs).ConclusionOur findings demonstrated that soluble rHSP90α increased the resistance of normal human monocytes to apoptosis and converted them into immunosuppressive MDSC via TLR4 signaling that stimulated PD-L1 and IDO-1 expression. Furthermore, patients with melanoma with high concentrations of HSP90α displayed increased PD-L1 expression on M-MDSC and reduced PFS after ICI therapy, suggesting HSP90α as a promising therapeutic target for overcoming immunosuppression in melanoma.
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Mishra, Alok K., Shahid Banday, Ravi Bharadwaj, Amjad Ali, Romana Rashid, Ankur Kulshreshtha, and Sunil K. Malonia. "Macrophages as a Potential Immunotherapeutic Target in Solid Cancers." Vaccines 11, no. 1 (December 26, 2022): 55. http://dx.doi.org/10.3390/vaccines11010055.
Повний текст джерелаАнотація:
The revolution in cancer immunotherapy over the last few decades has resulted in a paradigm shift in the clinical care of cancer. Most of the cancer immunotherapeutic regimens approved so far have relied on modulating the adaptive immune system. In recent years, strategies and approaches targeting the components of innate immunity have become widely recognized for their efficacy in targeting solid cancers. Macrophages are effector cells of the innate immune system, which can play a crucial role in the generation of anti-tumor immunity through their ability to phagocytose cancer cells and present tumor antigens to the cells of adaptive immunity. However, the macrophages that are recruited to the tumor microenvironment predominantly play pro-tumorigenic roles. Several strategies targeting pro-tumorigenic functions and harnessing the anti-tumorigenic properties of macrophages have shown promising results in preclinical studies, and a few of them have also advanced to clinical trials. In this review, we present a comprehensive overview of the pathobiology of TAMs and their role in the progression of solid malignancies. We discuss various mechanisms through which TAMs promote tumor progression, such as inflammation, genomic instability, tumor growth, cancer stem cell formation, angiogenesis, EMT and metastasis, tissue remodeling, and immunosuppression, etc. In addition, we also discuss potential therapeutic strategies for targeting TAMs and explore how macrophages can be used as a tool for next-generation immunotherapy for the treatment of solid malignancies.
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Sheybani, Natasha D., Alexandra R. Witter, Eric A. Thim, Hideo Yagita, Timothy N. J. Bullock, and Richard J. Price. "Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity." Journal for ImmunoTherapy of Cancer 8, no. 2 (August 2020): e001008. http://dx.doi.org/10.1136/jitc-2020-001008.
Повний текст джерелаАнотація:
BackgroundTriple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).MethodsWe applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1−/− mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.ResultsThe immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.ConclusionThermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.Trial registration numbersNCT03237572 and NCT04116320.
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Través, Paqui G., Alfonso Luque, and Sonsoles Hortelano. "Macrophages, Inflammation, and Tumor Suppressors: ARF, a New Player in the Game." Mediators of Inflammation 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/568783.
Повний текст джерелаАнотація:
The interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed.
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Schad, Sara, Daniel Hirschhorn-Cymerman, Sadna Budhu, Hong Zhong, Xia Yang, Taha Merghoub, and Jedd D. Wolchok. "Phosphatidylserine targeting antibody enhances anti-tumor activity of adoptive cell therapies in a mouse melanoma model." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 170.5. http://dx.doi.org/10.4049/jimmunol.204.supp.170.5.
Повний текст джерелаАнотація:
Abstract Adoptive cell therapy has emerged as a viable strategy to treat cancer. T cells that recognize tumor antigens can be reinvigorated ex-vivo or autologous T cells can be genetically modified to express anti-tumor T cell receptors (TCRs) or chimeric antigen receptors (CARs). However, once re-infused into patients, these tumor specific T cells are subjected to immunosuppressive signals within the tumor. A critical immune checkpoint within tumors is phosphatidylserine (PS), a phospholipid that is exposed on apoptotic cells and tumor cells. Innate cells exposed to PS secrete suppressive cytokines that can significantly impair the function of tumor specific T cells. Antibodies that target PS can reactivate anti-tumor immunity by reducing the number of MDSCs in tumors and promoting the maturation of functional APCs. Our lab has shown that the mouse chimeric version of PS Targeting monoclonal antibody Bavituximab (1N11), in combination with transgenic CD4+ T cells that recognize melanoma antigen Trp1, can regress advanced melanoma tumors in mice. Here, we demonstrate a 2nd generation CAR T cell, that binds Trp1 on the surface of B16 melanoma, in combination with 1N11 can improve anti-tumor activity and survival in B16 tumor bearing mice. Flow cytometry analysis of immune responses in the tumor of mice treated with tumor specific T cells and 1N11 shows a decrease in M2 macrophages and FoxP3+ regulatory T cells. These findings highlight that diminishing suppressive mechanisms locally with PS targeting can enhance the efficacy of transgenic TCR and CAR T cells to improve the outcome in patients with advanced-stage melanoma. Our studies may inform the design of clinical trials combining PS Targeting antibodies with CAR T cell therapy in solid tumors.
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Dong, Juan, Cassandra Gilmore, Hieu Ta, Keman Zhang, Sarah Stone, and Li Wang. "501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A536. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0501.
Повний текст джерелаАнотація:
BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.
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Yu, Xiaolu, Yiru Long, Binfan Chen, Yongliang Tong, Mengwen Shan, Xiaomin Jia, Chao Hu, et al. "PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way." Journal for ImmunoTherapy of Cancer 10, no. 10 (October 2022): e004590. http://dx.doi.org/10.1136/jitc-2022-004590.
Повний текст джерелаАнотація:
BackgroundVarious tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed.MethodsPD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels.ResultsThe screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either ‘hot’ or ‘cold’ tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8+T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1.ConclusionsThe novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development.
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Hurez, Vincent, Vinh Dao, Aijie Liu, Srilakshmi Pandeswara, Jonathan Gelfond, Lishi Sun, Robert Svatek, et al. "Mammalian target of rapamycin inhibition with enterically given rapamycin alters immunity and gut flora in young and aged wild type mice and extends life of immunodeficient mice (IRC8P.452)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 129.16. http://dx.doi.org/10.4049/jimmunol.194.supp.129.16.
Повний текст джерелаАнотація:
Abstract mTOR regulates many important immune processes. Interest in immune effects of mTOR inhibitors is heightened by recent findings of ability to boost specific immunity and vaccine response in elderly humans, treat cancers and autoimmunity, and extend life and healthspan in mice, suggesting important new clinical applications. However, immune toxicity concerns for long-term mTOR inhibition, particularly immunosuppression, persist. We comprehensively analyzed immune effects of long-term rapamycin in mice. Gene expression profiling of purified T and B cells (CD4+PD1+, CD4+PD1-, CD8+PD1+, CD8+PD1-, B220+), CD11b+CD11c- myeloid cells and CD11c+ dendritic cells showed numerous, novel changes in genes affecting differentiation, function, homeostasis, migration, exhaustion, cell death and inflammation. Novel effects on Th9, Th22 and Tfh differentiation were seen as was improved function of exhausted PD1+ T cells (supported by human clinical data) and increased numbers and function of innate lymphoid cells. Immune functions relevant to cancer, infections, aging and inflammation, and innate lymphoid cell effects were validated in vitro and in vivo. eRapa prolonged life in RAG KO mice (without T or B cells) >12x and in IFN-γ KO mice >3x over wild type mice, supporting mTOR suppression immune effects mitigating disease as a mechanism for longevity extension. Metagenomic effects were linked to immune outcomes. Our data demonstrate novel mTOR immune effects meriting further investigations.
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Cheng, An Ning, Li-Chun Cheng, Cheng-Liang Kuo, Yu Kang Lo, Han-Yu Chou, Chung-Hsing Chen, Yi-Hao Wang, Tsung-Hsien Chuang, Shih-Jung Cheng, and Alan Yueh-Luen Lee. "Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles." Journal for ImmunoTherapy of Cancer 8, no. 2 (December 2020): e001372. http://dx.doi.org/10.1136/jitc-2020-001372.
Повний текст джерелаАнотація:
BackgroundMitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME).MethodsWe explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME.ResultsWe found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME.ConclusionsThe levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.
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Bendell, Johanna, Wells Messersmith, Drew Rasco, Andrea Wang-Gillam, Wungki Park, Lei Zhou, Laura Carter, et al. "388 Preliminary results from KEYNOTE-A36, a study of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab or chemotherapy in specified advanced solid tumors." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A413. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0388.
Повний текст джерелаАнотація:
BackgroundGB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342)MethodsThis study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis.ResultsAs of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing.ConclusionsDose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging.Ethics ApprovalThis ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.ReferencePanni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).
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Voutouri, Chrysovalantis, Corey C. Hardin, Vivek Naranbhai, Mohammad R. Nikmaneshi, Melin J. Khandekar, Justin F. Gainor, Triantafyllos Stylianopoulos, Lance L. Munn, and Rakesh K. Jain. "Abstract A64: Mechanistic model for booster doses effectiveness in healthy, cancer and immunosuppressed patients infected with SARS-CoV-2." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A64. http://dx.doi.org/10.1158/2326-6074.tumimm22-a64.
Повний текст джерелаАнотація:
Abstract Introduction: Current SARS-CoV-2 vaccines are effective at preventing COVID-19 or limiting disease severity in healthy individuals, but effectiveness is lower among patients with cancer or immunosuppression. Vaccine effectiveness wanes with time and varies by vaccine type. Moreover, current vaccines are based on the ancestral SARS-CoV-2 spike protein sequence and emerging viral variants evade vaccine induced immunity. Booster doses partially overcome these issues, but there are limited clinical data on the durability of protection afforded by boosters – especially against SARS-CoV-2 variants.Methods: Here we describe a mechanistic mathematical model for vaccination-induced immunity and use it to predict vaccine effectiveness taking into account current and possible future viral, host and vaccine characteristics. Crucially, this allows predictions over time frames currently not reported in the clinical literature. The model incorporates the infection of lung epithelium by SARS-CoV-2, the response of innate and adaptive immune cells to infection, the production of pro-and anti-inflammatory cytokines, the activation of the coagulation cascade, as well as the effects of cancer cells on the lung and on the immune response. The model further accounts for the interactions between the virus, the immune cells and the tumor cells as well as for vaccination-induced immunity.Results: Model predictions were validated with clinical data. The model predicts that for healthy individuals vaccinated and boosted with mRNA-1273, BNT-162b2a, and Ad26.COV2.S, robust immunogenicity against the ancestral and delta variant extends beyond a year. Immunogenicity is also enhanced following booster vaccination in patients with cancer on various anti-cancer therapies, including immunotherapy, and for patients without cancer on immunosuppressive agents.Conclusion: Our model predicts that ³1 booster doses will be required for these individuals to maintain protective immunity. Furthermore, for immunosuppressed individuals, simulated new SARS-CoV2 variants with enhanced ability to bind to target cells, faster replication or reduced immunogenicity could lead to breakthrough infections even after a single booster dose. Modelling data such as these may be used to anticipate and plan for future vaccination needs. Citation Format: Chrysovalantis Voutouri, Corey C Hardin, Vivek Naranbhai, Mohammad R. Nikmaneshi, Melin J. Khandekar, Justin F Gainor, Triantafyllos Stylianopoulos, Lance L. Munn, Rakesh K. Jain. Mechanistic model for booster doses effectiveness in healthy, cancer and immunosuppressed patients infected with SARS-CoV-2 [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A64.
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Sana, Madiha, Muhammad Rashid, Imran Rashid, Haroon Akbar, Jorge E. Gomez-Marin, and Isabelle Dimier-Poisson. "Immune response against toxoplasmosis—some recent updates RH: Toxoplasma gondii immune response." International Journal of Immunopathology and Pharmacology 36 (January 2022): 039463202210784. http://dx.doi.org/10.1177/03946320221078436.
Повний текст джерелаАнотація:
Aims Cytokines, soluble mediators of immunity, are key factors of the innate and adaptive immune system. They are secreted from and interact with various types of immune cells to manipulate host body’s immune cell physiology for a counter-attack on the foreign body. A study was designed to explore the mechanism of Toxoplasma gondii ( T. gondii) resistance from host immune response. Methods and results The published data on aspect of host (murine and human) immune response against T. gondii was taken from Google scholar and PubMed. Most relevant literature was included in this study. The basic mechanism of immune response starts from the interactions of antigens with host immune cells to trigger the production of cytokines (pro-inflammatory and anti-inflammatory) which then act by forming a cytokinome (network of cytokine). Their secretory equilibrium is essential for endowing resistance to the host against infectious diseases, particularly toxoplasmosis. A narrow balance lying between Th1, Th2, and Th17 cytokines (as demonstrated until now) is essential for the development of resistance against T. gondii as well as for the survival of host. Excessive production of pro-inflammatory cytokines leads to tissue damage resulting in the production of anti-inflammatory cytokines which enhances the proliferation of Toxoplasma. Stress and other infectious diseases (human immunodeficiency virus (HIV)) that weaken the host immunity particularly the cellular component, make the host susceptible to toxoplasmosis especially in pregnant women. Conclusion The current review findings state that in vitro harvesting of IL12 from DCs, Np and MΦ upon exposure with T. gondii might be a source for therapeutic use in toxoplasmosis. Current review also suggests that therapeutic interventions leading to up-regulation/supplementation of SOCS-3, IL12, and IFNγ to the infected host could be a solution to sterile immunity against T. gondii infection. This would be of interest particularly in patients passing through immunosuppression owing to any reason like the ones receiving anti-cancer therapy, the ones undergoing immunosuppressive therapy for graft/transplantation, the ones suffering from immunodeficiency virus (HIV) or having AIDS. Another imortant suggestion is to launch the efforts for a vaccine based on GRA6Nt or other similar antigens of T. gondii as a probable tool to destroy tissue cysts.
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Peng, Li, Lizhi Cao, Sujata Nerle, Robert LeBlanc, Abhishek Das, Sandip Shelke, Autumn Turner, et al. "843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A884. http://dx.doi.org/10.1136/jitc-2021-sitc2021.843.
Повний текст джерелаАнотація:
BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (<0.1 g/L) under similar conditions, respectively. We demonstrated that Bi-Sialidase led to dose-dependent desialylation of immune cells and potentiated T-cell immunity, without impacting NK, macrophage, or neutrophil activation by desialylating immune cells. Activated and exhausted T cells upregulated surface sialoglycans and Bi-Sialidase-mediated desialylation reinvigorated exhausted-like T cells as measured by IFNg production. Bi-Sialidase treatment also enhanced DC priming and activation of naïve T cells by desialylating both T cells and DCs. Furthermore, Bi-Sialidase showed single-agent antitumor activity in multiple mouse tumor models, including MC38, CT26, A20, and B16F10. Importantly, Bi-Sialidase did not cause cytokine release in human PBMC assays and was tolerated to up to 100 mg/kg in rats and NHPs, demonstrating a wide safety margin.ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.
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Yang, Tian-Hui, Karen Clise-Dwyer, Gheath Alatrash, Kathryn Ruisaard, Shoudan Liang, and Jeffrey J. Molldrem. "Membrane-Associated Proteinase 3 on Granulocytes and Myeloid Leukemia Mediates Reversible Inhibition of T Cell Proliferation." Blood 118, no. 21 (November 18, 2011): 1916. http://dx.doi.org/10.1182/blood.v118.21.1916.1916.
Повний текст джерелаАнотація:
Abstract Abstract 1916 Proteinase 3 (P3), a serine protease constitutively expressed in primary granules and on the membrane of some resting granulocytes, is the target of T cell-mediated autoimmunity in Wegener's granulomatosis (WG) and of anti-leukemia immunity mediated by PR1 (VLQELNVTV)-specific cytotoxic T lymphocytes (PR1-CTL). We have shown that soluble P3 is increased by 5-fold in sera from acute myeloid leukemia (AML) patients compared to healthy controls, and soluble P3 mediates enzyme-independent inhibition of T-cell proliferation. Moreover, tumor-associated neutrophils (TANs) are associated with a poor prognosis in a number of cancers including renal cell carcinoma and lung cancer, and P3 is also over-expressed in a variety of AML and chronic myeloid leukemia (CML). Therefore, we hypothesized that membrane-bound P3 (mP3) may similarly regulate adaptive immunity by suppressing T-cell proliferation. To study this, T cells from healthy donors were labeled with the membrane dye CFSE and stimulated with anti-CD3 and anti-CD28 in the presence or absence of mP3-expressing PMNs for five days. The percentage of proliferating cells was determined by flow cytometry. Proliferation of autologous CD8+ and CD4+ T cells was significantly inhibited by 75% and 72%, respectively, when PMNs were co-incubated with lymphocytes at a ratio of 3:1, and by > 90% at 5:1. This cell contact-dependent inhibitory effect was limited to PMN since PBMCs added to lymphocytes in place of PMNs at 5:1 had no effect on T cell proliferation. To determine whether the inhibitory effect was specifically mediated by mP3, we FAC-sorted CD177+PMNs and CD177−PMNs to obtain highly purified (>98%) mP3+ and mP3− PMNs, respectively, because CD177 and mP3 are co-expressed on same subset of resting PMNs. At a ratio of 3:1 (CD177+PMNs or CD177−PMNs to lymphocytes), mP3+PMNs mediated > 75% growth inhibition of both CD8+ and CD4+ T cells compared to < 55% inhibition by mP3−PMNs (p<0.05). Furthermore, the inhibitory effect of mP3+PMNs on T cell proliferation was blocked (< 10% inhibition of proliferation) by anti-P3 but not by isotype control mAb. The inhibitory effect of mP3 was enzyme-independent because Elafin or α1-anti-trypsin did not affect inhibition by mP3+PMNs. In addition, mP3-mediated inhibition was fully reversible as T cells proliferated normally with anti-CD3/anti-CD28 stimulation after PMNs were removed from co-culture. Similarly, mP3+AML blasts inhibited autologous CD8+ and CD4+ T cell proliferation by 50% and 30%, respectively, at a 2:1 ratio of AML blasts: lymphocytes. Interestingly, bone marrow myeloid derived suppressor cells (MDSC) from leukemia patients express significantly higher mP3 (79.4±5.23% (mean±SEM, n=7)), compared to 22.4±11.55% mP3 on MDSC from healthy donors (p= 0.0007, n=3). Taken together, these data support an important new function of membrane-bound P3 on innate immune cells and leukemia in controlling adaptive T cell immunity. These findings suggest a novel mechanism whereby neutrophils could promote tumor growth in vivo through contact-mediated suppression of tumor-infiltrating lymphocytes by mP3 or by soluble P3 secreted by activated TANs in cancer and myeloid leukemia. Thus, targeting P3 with anti-P3 antibodies may be explored as a novel therapeutic strategy for leukemia and other cancers. Disclosures: No relevant conflicts of interest to declare.
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Gao, Yuting, Hao Zhou, Gege Liu, Junlu Wu, Yi Yuan, and Anquan Shang. "Tumor Microenvironment: Lactic Acid Promotes Tumor Development." Journal of Immunology Research 2022 (June 12, 2022): 1–8. http://dx.doi.org/10.1155/2022/3119375.
Повний текст джерелаАнотація:
Lactic acid is a “metabolic waste” product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells’ effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.
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Hanamura, Toru, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Banri Tsuda, Takuho Okamura, et al. "Abstract P4-04-09: Systematic analysis of immune cell composition revealed immunological profile of breast cancer microenvironment represented by histologically assessed tumor-infiltrating lymphocyte and PD-L1 expression." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–04–09—P4–04–09. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-04-09.
Повний текст джерелаАнотація:
Abstract Purpose. The clinical use of immune checkpoint inhibitors for multiple cancers has attracted attention in tumor immunology. Emerging evidence suggests that a better understanding of tumor immunology will lead to the development of new treatment strategies or the effective use of existing therapies. Histologically assessed tumor-infiltrating lymphocytes (hTIL) and programmed cell death 1 ligand 1 (hPD-L1) have been established as prognostic or predictive biomarkers in certain subsets of breast cancer. In addition, researchers have shifted their focus to the various immune cell subsets that make up TILs. However, the complexity of multiple types of immune cells in TIL or PD-L1 expressing cells is not fully understood. In this analysis, the immune cell fraction in breast cancer tissue and blood was evaluated by multicolor flow cytometry (FCM) to analyze the association between them and hTIL and hPD-L1. Methods. Forty-five tumor and 18 blood samples were collected from breast cancer patients. The leukocyte count, proportion of 11 types of immune cell fraction, and PD-L1 expression of each fraction were evaluated by FCM for both tumor and blood samples. The immune cell fractions are classified into the following categories based on the expression of cell surface markers: leukocyte, total T cell (total T), CD4+ T cell (CD4+ T), CD8+ T cell (CD8+T), B cell (B), monocyte/macrophage (Mo/Mϕ), nonclassical monocyte (CD16+Mo), myeloid-derived suppressor cells (MDSC), dendritic cells (DC), myeloid dendritic cells (mDC), natural killer cells (NK), minor NK, and natural killer T cells (NKT). hTIL, and hPD-L1 were evaluated by H-E staining and immunohistochemistry, respectively. Results. The mean density and interquartile range of tumor-infiltrating leukocytes were similar to those in previous report. For the immune cell fraction in the leukocytes of tumor tissue, the main population consisted of CD8+T and CD4+T, which showed a similar trend to that of blood. The proportions of DC, mDC, NK, and minor NK in tumor tissues were positively correlated with those of blood. When the percentage of each immune cell fraction of tumor tissue and that of blood were compared, the proportions of DC, mDC, and minor NK were significantly higher in tumor tissues than those in blood samples, and the proportions of CD4+T and NK were significantly lower in tumor tissue than in blood. No significant association was found between blood immune cell composition and hTIL or hPD-L1. High hTIL levels were associated with high leukocyte infiltration, high proportions of CD4+ T and CD8+ T, and a low proportion of NK and NKT in the tumor tissue. When PD-L1 positive cell percentage of each immune cell fraction was compared between the tumor tissue and blood, PD-L1 positive ratios were significantly higher in tumor tissue than in blood for all lineages except for lymphoid fractions. For tumor tissues, PD-L1 expression was high in Mo/Mϕ, CD16+Mo, MDSC, DC, and mDC. hPD-L1 positivity was associated with PD-L1 expression in Mo/Mϕ, CD16+Mo, DC, and mDC. Conclusion. Comprehensive analysis of the immune cell fractions revealed the immunological profile of breast cancer tissue represented by hTIL or hPD-L1. Our data indicate that hTIL not only reflects the amount of immune cell infiltration but also reflects a state in which acquired immunity is activated relative to innate immunity. Non-B cell antigen-presenting cell fractions such as Mo/Mϕ, CD16+ Mo, MDSC, DC, and mDC were primarily involved in the PD-L1 pathway in breast cancer microenvironments. In addition, hPD-L1 reflects PD-L1 expression in these immune cell fractions. Our data provide a basic understanding of the immune response in the breast cancer microenvironment and contribute to further development of tumor immunology. Citation Format: Toru Hanamura, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Banri Tsuda, Takuho Okamura, Nobue Kumaki, Katsuto Hozumi, Naoki Harada, Takaiki Iwamoto, Chikako Honda, Sasagu Kurozumi, Naoki Niikura. Systematic analysis of immune cell composition revealed immunological profile of breast cancer microenvironment represented by histologically assessed tumor-infiltrating lymphocyte and PD-L1 expression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-09.
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Lupo, Kyle, and Sandro Matosevic. "130 Engineered natural killer cells reactively block TIGIT and CD73 in the GBM microenvironment." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A139. http://dx.doi.org/10.1136/jitc-2021-sitc2021.130.
Повний текст джерелаАнотація:
BackgroundNatural killer (NK) cells have emerged as promising effectors to target GBM and other solid tumors through genetic modifications and ex vivo manipulation. However, immunosuppressive conditions within the tumor microenvironment (TME) and interactions between NK cell activating and inhibitory receptors further complicate NK cell-based treatments. In particular, the T cell immunoreceptor with Ig and ITIM domains (TIGIT) is expressed on NK cells and interacts with CD155 to induce immunosuppression of NK cell cytolytic functions.1 2 Although CD155 also binds with activating receptors DNAM-1 and CD96 on NK cells, spurring NK cell activity, TIGIT has predominantly been reported as having an inhibitory effect on NK cells.3–5 Further, tumor cells release of high levels of ATP extracellularly. While intracellular ATP is necessary for cell metabolism, extracellular ATP is converted into adenosine (ADO) by ectonucleotidases CD39 and CD73, both overexpressed on GBM and other solid tumors.6 Extracellular ADO induces immunometabolic suppression of NK cells through binding with A2A adenosine receptors (A2ARs) on NK cells, suppressing cytokine secretion, proliferation, and other functional activities.7–9 We found that TIGIT and CD73 are effective combination targets in GBM for both primary and iPSC-derived NK cells.MethodsIn order to effectively target immunometabolic reprogramming induced by CD73-produced adenosine and the immunosuppressive TIGIT-CD155 axis, we have engineered NK cells to concomitantly target CD155 and CD73-induced immunosuppression on GBM using a tumor-responsive genetic construct based on the synNotch signaling system. The construct is capable of blocking the immunosuppressive CD155/TIGIT interaction, and, upon binding, release a CD73-blocking scFv to inhibit the accumulation of extracellular ADO and mitigate immunosuppression of NK cells. Such localized response enhances specificity and reduces off-target effects of NK-based targeting.ResultsPrimary NK cells and iPSC-derived NK cells were successfully engineered to express the synthetic TIGIT-synNotch construct, measured through expression of TIGIT. To evaluate the functionality of engineered NK cells against GBM targets, we tested the cytotoxicity of our engineered NK cells against a primary, patient-derived GBM cell line, GBM43. Overall, cytolytic function of engineered NK cells against GBM was significantly higher than that of non-engineered NK cells, with or without CD73 (10 ug/mL) and TIGIT (50 ug/mL) antibodies, for E:T ratios of 5:1 and 10:1, demonstrating the functional efficacy of our genetic construct.ConclusionsOverall, we have shown that co-targeting CD155 and CD73 in a localized, responsive manner can dampen immunosuppression and significantly enhance the killing potential of engineered NK cells against aggressive patient-derived GBM tumors.ReferencesZhang B, et al. Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155. Cancer Immunol Immunother 2016;65:305–314.Lupo KB & Matosevic S. CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma. J Hematol Oncol 2020;13:76.Hung AL, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. OncoImmunology 2018; e1466769. doi:10.1080/2162402X.2018.1466769.Mahnke K & Enk, AH. TIGIT-CD155 Interactions in Melanoma: A Novel Co-Inhibitory Pathway with Potential for Clinical Intervention. Journal of Investigative Dermatology 2016; 136, 9–11.Stanietsky N, et al. Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR: Innate immunity. Eur J Immunol 2013; 43:2138–2150.Chambers AM, et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front Immunol 2018;9:2533.Chambers AM, Lupo KB & Matosevic S. Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells. Front Immunol 2018;9:2517.Chambers AM. et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front Immunol 2018;9:2533.Wang J, Lupo KB, Chambers AM & Matosevic S. Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J Immunotherapy Cancer 2018;6:136.Ethics ApprovalPrimary human NK cells were obtained from healthy adult donors approved under Purdue University’s Institutional Review Board (IRB) (IRB-approved protocol #1804020540). Donors gave written informed consent prior to taking part in the study.
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Ota, Shuichi, and Masahiro Ogasawara. "Vaccination Of Malignant Lymphoma Patients With WT1 Peptide-Pulsed Dendritic Cells Induces Immunological and Clinical Responses: A Pilot Study." Blood 122, no. 21 (November 15, 2013): 4403. http://dx.doi.org/10.1182/blood.v122.21.4403.4403.
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Abstract Background With the advent of monoclonal antibodies such as rituximab, the duration of remission and overall survival in B-cell non-Hodgkin’s lymphoma has improved significantly. However, new therapeutic approaches are needed for patients with refractory disease. Active immunizations using dendritic cells (DCs) loaded with ideotype proteins or tumor lysates have shown safety with limited efficacy. Wilms’ tumor 1 (WT1) gene is frequently overexpressed in lymphoma and is considered to be one of the ideal tumor antigens for cancer immunotherapy. In the present pilot study, we treated lymphoma patients with WT1 peptide-pulsed DC and examined safety, clinical and immunological responses to the vaccination. Methods 5 HLA-A*24:02(A24)+patients (4 males, 1 female; aged 51-90 years; 2 with diffuse large B cell lymphoma, 1 with mantle cell lymphoma, 1 with follicular lymphoma and 1 with peripheral T cell lymphoma) with relapsed or refractory disease were enrolled in the present study. Autologous DCs were generated from patients' peripheral blood monocytes which were separated by an adherence technique from mononuclear cells collected by apheresis. Monocytes were cultured with GM-CSF and IL-4 followed by maturation with OK432 and PGE2. HLA-A24-restricted, modified 9-mer WT1 peptide-loaded mature DCs were administered intradermally every 2 weeks 5-7 times in combination with OK432. Induction of vaccine-induced T cell responses was monitored by a HLA-tetramer assay and a flow cytometry analysis. Cytotoxicity against WT1 peptide pulsed target cells was tested in a LDH release assay. Results The treatment was well tolerated and none of the patients experienced more than grade 2 adverse events during the treatment period. The most common adverse events were mild, transient erythema at injection sites and low grade fever. Of 5 patients, 1 had CR, 1 had PR, 2 had SD and 1 had PD following one course of the treatment. Survival of patients achieving CR, PR or SD (responder) after one course of DC vaccination was longer than those who did not respond to the treatment. Duration of survival in responders was 56, 32, 24 and 19 months after initiation of therapy. Three responders are still alive in remission. Increase in positivity of WT1-specific CD8+ T cells was observed in responders after one course of treatment; the percentage of HLA-A24 restricted WT1 tetramer positive cells was 0.12±0.12% before vaccination, it increased to 6.82±10.2% after the first course. WT1 tetramer positivity in one of the responding patients who received 3 courses of vaccination increased from 0.06% to 24.5% following one course of vaccination. High level of positivity persisted thereafter (14.6% and 14.6% after second and third course, respectively). Cytotoxic T cells (CTLs) generated by in vitro stimulation with WT1 peptide showed cytotoxic activity in an LDH release assay; percent specific lysis against WT1 peptide-pulsed HLA-A24+ target was 64.8% at effector/target ratio 30 to1. CTL did not lyse irrelevant HIV peptide-pulsed HLA-A24+ target and WT1 peptide-pulsed HLA-A24- target, demonstrating antigen specificity and HLA restriction. Absolute number of lymphocytes, CD3+ T cells, CD4/CD8 ratio and NK cells increased by 1.10±0.38, 2.03±1.78, 1.27±0.36, 1.31±0.74 fold, respectively, following the first course of DC vaccination in responders. On the other hand, absolute number of CD4+CD25+Foxp3+ regulatory T cells (Treg) decreased by 50.7%. Lin-CD33+HLA-DR- myeloid-derived suppressor cells (MDSC) decreased from 17.8%±10.1 to 9.0±2.5% (38.3% reduction). Similarly, monocytic MDSC (CD14+HLA-DRlow/-) and granurocytic MDSC (CD15+CD33+) decreased by 34.4% and 34.0%, respectively, indicating that DC vaccination may contribute to the reversal of immunosuppression by Treg and MDSC. Conclusions The present study demonstrated that a vaccination with WT1 peptide-pulsed DC was well tolerated and no serious adverse event was observed. DC vaccination elicits both innate and acquired cellular immune responses correlated with clinical effects. These results suggest WT1 peptide-pulsed DC vaccination might be a promising novel strategy for the treatment of malignant lymphoma patients with relapsed or refractory disease. Disclosures: No relevant conflicts of interest to declare.
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Huang, Tao, Caroline Bonnans, Maria Jose Costa, Azita Tabrizi, Jing-Tyan Ma, Jingjing Xie, Heyu Chen, et al. "304 Antagonistic antibodies targeting LAIR1 enhance T lymphocyte activation and promote inflammatory phenotypes in myeloid cells." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A327. http://dx.doi.org/10.1136/jitc-2021-sitc2021.304.
Повний текст джерелаАнотація:
BackgroundThe Leukocyte Associated Immunoglobulin-like Receptor 1 (LAIR1) is an immune inhibitory transmembrane glycoprotein expressed on lymphocytes and myeloid cells. The known ligands for LAIR1 are proteins containing collagen-like domains including collagen, complement component 1q (C1q), and stromal protein Colec12.1 2 3 Myeloid-derived suppressor cells (MDSC), tumor associated macrophages (TAMs), as well as collagens, are important contributors of the immune-suppressive tumor microenvironment, and LAIR1 expression is negatively correlated with patient survival in many solid tumors.4 These findings prompt us to investigate LAIR1 as a novel immuno-oncology target in collagen-rich tumors. Utilizing LAIR1 antagonist antibodies, we aim to mobilize anti-tumor immunity by changing the collagen-induced tolerogenic state of the immune cells into proinflammatory.MethodsThe mRNA expression levels of LAIR1, collagen, and C1q in diverse human cancers were analyzed using the TCGA database. LAIR1 protein expression on tumor infiltrated immune cells were measured by flow cytometry. Human tumor samples were obtained from Cooperative Human Tissue Network (CHTN) by the National Cancer Institute (NCI). Purified human T cells from healthy donors were stimulated with immobilized anti-CD3 in the presence of plate-coated human collagen I. Human monocyte-derived macrophages and dendritic cells (DC) were differentiated with M-CSF+IL-4 or GM-CSF+IL-4, respectively. Immune cell phenotypes were assessed by flow cytometry and cytokine secretion by Luminex.ResultsAnalysis of the TCGA database using signature genes specific to macrophages, T cells, DCs, and natural killer (NK) cells demonstrate that LAIR1 is highly expressed in most macrophage-infiltrated tumors and certain T cell-enriched tumors. LAIR1 and collagen are co-expressed at high levels in multiple macrophage-enriched tumors. Flow cytometry analysis of infiltrated immune cells from fresh tumor tissues showed that the highest level of LAIR1 protein expression was detected on TAMs, followed by monocytes, monocytic MDSCs, DCs, and lymphocytes. In vitro, LAIR1 antagonizing antibodies enhanced T-cell activation, proliferation, and IFNγ and TNFα production in comparison to isotype controls in the presence of collagen. Blocking LAIR1 interaction with collagen also decreased the expression of M2 markers such as PD-L1 and CD209 on monocyte-derived M2 macrophages. Additionally, treatment of monocyte-derived DCs by these antibodies increased the expression of the co-stimulatory protein CD86 and promoted the release of IL-12, a crucial cytokine for lymphocyte activation.ConclusionsThese in vitro data suggest that LAIR1 blockade could potentially reverse T-cell and myeloid immunosuppression mediated by collagen, demonstrating the therapeutic potential of anti-LAIR1 antagonistic antibodies.ReferencesMeyaard L. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol 2008;83:799–803.Son M, et al. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. PNAS 2012;109:3160–3167.Keerthivasan S, et al. Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1. Immunity 2021;54:1511–1526.Xu L, et al. Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1. OncoImmunology 2020;9:e17404771–e17404779.
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Lee, Je-Jung, Tan-Huy Chu, Manh-Cuong Vo, Hye-Sung Park, Thangaraj Jaya Lakshmi, Seo-Yeon Ahn, Ga-Young Song, Sung-Hoon Jung, and Hyeoung-Joon Kim. "A Combination Therapy with Dendritic Cells, Pomalidomide and Programmed Death-Ligand 1 Blockade Exerts a Potent Antitumor Immunity in a Murine Model of Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 1819. http://dx.doi.org/10.1182/blood-2019-127964.
Повний текст джерелаАнотація:
Multiple myeloma (MM) is the second-most-common hematologic malignancy, and develops from clonal malignant plasma cells within bone marrow. Despite tremendous improvements in therapeutic strategies (e.g. stem cell transplantation, immune-modulatory drugs (IMiDs), proteasome inhibitors, and, more recently, immunotherapy), which have led to improved responses to treatment and overall survival, most patients eventually relapse. We have previously shown that the immunization with tumor antigen-loaded dendritic cells (DCs) and pomalidomide/dexamethasone synergistically potentiates the enhancing the antitumor immunity in a myeloma mouse model. In the present study, we investigated whether a DC-based vaccine combined with pomalidomide and PD-L1 blockade has a synergistic effect in a murine MM model. MOPC-315 cell lines were injected subcutaneously to establish MM-bearing mice. Four test groups were used to mimic the clinical protocol: (1) PBS control, (2) DCs + pomalidomide/dexamethasone, (3) pomalidomide/dexamethasone + PD-L1 blockade, and (4) DCs + pomalidomide/dexamethasone + PD-L1 blockade. After treatment, preclinical response and in vitro immunological responses were evaluated. The study was designed to closely mimic the clinical MM treatment protocol and clearly demonstrated that combination treatment with DCs + pomalidomide with dexamethasone + PD-L1 blockade more strongly inhibited MM tumor growth. Consequently, the mice treated with DCs + pomalidomide with dexamethasone + PD-L1 blockade displayed markedly induced tumor regression and significantly prolonged survival, as well as very strong anti-myeloma CTL responses and increased numbers of effector cells (such as CD4+ T cells, CD8+ T cells, memory T cells, NK cells and M1 macrophages) associated with antitumor effects. This treatment also effectively decreased the proportions of suppressor cells, including MDSCs, Tregs and M2 macrophages, in the spleen and tumor microenvironment of treated mice. Tregs, MDSCs and M2 macrophages play crucial roles in immunosuppression and tolerance, which are mediated by tumor-secreted cytokines. The inhibition of Tregs, MDSC and M2 macrophage accumulation may enhance systemic cell-mediated immunity through the activation of DCs or CTLs. Importantly, treatment with pomalidomide with dexamethasone + PD-L1 blockade led to decreased expression of PD-L1 and CTLA-4 in treated mice, which further induced effector cell infiltration of the tumor microenvironment. Moreover, DCs + pomalidomide with dexamethasone + PD-L1 blockade induced the activation of cell-mediated immunity by increasing Th1-specific immune responses, as evidenced by the increased production of IFN-γ and a decrease in the regulatory-specific immune response, as evidenced by the decreased production of TGF-β, IL-10 and VEGF in the spleen and tumor microenvironment. These findings show that inducing the systemic immune response represent a means of treating myeloma. Immunotherapy clearly represents a revolution in cancer care, and promising responses have been shown to various treatments, particularly immune checkpoint inhibitors, IMiDs, DCs and CAR T cells. However, not all patients are responsive to current immunotherapies, and among those patients who do respond, the effects are not always long-lasting. Thus, combination approaches are a cornerstone of cancer therapy for improving patient outcomes in MM. This study demonstrated that the combination of DC vaccination + pomalidomide with dexamethasone + PD-L1 blockade synergistically enhances myeloma immune responses to inhibit tumor growth, restores and enhances host immune effector cells, and reduces the generation of immune suppressor cells in MM. This study provides a framework for developing and understanding the role of immunotherapeutic modalities employing DCs, pomalidomide and PD-L1 blockade to inhibit tumor growth and restore immune function in myeloma-bearing mice. Figure Disclosures No relevant conflicts of interest to declare.
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Hao, Xiaoxiao, Chao Zhang, Timothy N. Trotter, Pramod S. Gowda, and Yang Yang. "Abstract A12: Osteocyte apoptosis induces an immunosuppressive microenvironment in bone marrow and promotes myeloma chemoresistance." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A12. http://dx.doi.org/10.1158/2326-6074.tumimm22-a12.
Повний текст джерелаАнотація:
Abstract Multiple myeloma (MM) is a plasma-cell malignancy that grows in bone marrow (BM). MM resistance to chemotherapy is a major cause of patient mortality. Osteocytes are the most abundant cell type in bone. We have recently demonstrated that MM cells induce osteocyte apoptosis. While the mechanisms responsible for MM-induced osteocyte apoptosis have been described, it is unknown whether apoptotic osteocytes provide feedback that regulates MM cells. To study this, we developed a unique syngenic animal model of murine MM in which osteocyte apoptosis can be induced through targeted expression of human diphtheria toxin receptor (DTR) in osteocytes and subsequent injection of DT. In our current study, we used this DTR mouse model to access the impact of osteocyte apoptosis on MM cell response to the treatments of bortezomib (BTZ) and dexamethasone (DEX), two frontline anti-MM drugs. Eight-week-old DTR mice were i.p. injected with either PBS as control or DT (12.5µg/kg) to induce apoptosis in osteocytes. One week later, DTR+PBS and DTR+DT mice were injected with 106 5TGM1-luc MM cells via tail vein (n=21/group) and after 4 days, randomly assigned to treatment for 4 weeks with PBS or DEX (i.p. 1mg/kg/day) or BTZ (i.p. 0.5mg/kg/3 days) (n=7/group). Bioluminescence imaging and serum IgG2bκ (a soluble marker of 5TGM1-luc MM cells) ELISA, performed after 4-week treatment, demonstrated that osteocyte apoptosis promotes tumor growth in BM; DEX or BTZ treatment significantly inhibited tumor growth in DTR+PBS mice but not in DTR+DT mice. Flow cytometry analysis of 5TGM1-Luc MM cells in the BM further revealed that DEX and BTZ failed to induce MM cell apoptosis/death in DTR+DT mice, in contrast to the effectiveness observed in DTR+PBS mice. Analyses of BM cells harvested from these mice showed that compared with tumor-bearing DTR+PBS+PBS mice, tumor-bearing DTR+DT+PBS mice had significantly higher concentration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and fewer effective CD8+ T cells in the BM. These CD8+ T cells also have a lower expression of the cytotoxic molecules granzyme B and IFN-γ. Importantly, DEX or BTZ treatment improved anti-MM immunity in the BM of tumor-bearing DTR+PBS mice but failed in tumor-bearing OB-Runx2-/- mice. Gemcitabine (GEM) is a FDA-approved anti-cancer agent and MDSC inhibitor used in the treatment of solid tumors but not commonly used in MM therapy. To confirm that MDSCs indeed promote osteocyte-apoptosis-induced MM resistance to DEX/BTZ and to determine if depletion of MDSCs can overcome this resistance, we treated 5TGM1-Luc tumor-bearing DTR+DT mice with PBS, GEM (i.p. 30 mg/kg/week), GEM+DEX or GEM+BTZ for 4 weeks. Bioluminescence imaging and serum IgG2bκ ELISA demonstrated that GEM+DEX or GEM+BTZ reversed MM resistance to DEX and BTZ and resulted in the greatest reduction in tumor burden among all treatments. In conclusion, our findings demonstrate that osteocyte apoptosis promotes MM cell resistance to DEX and BTZ and BM immunosuppression induced by osteocyte apoptosis plays a role in this event. Citation Format: Xiaoxiao Hao, Chao Zhang, Timothy N Trotter, Pramod S Gowda, Yang Yang. Osteocyte apoptosis induces an immunosuppressive microenvironment in bone marrow and promotes myeloma chemoresistance [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A12.
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Castella, Barbara, Myriam Foglietta, Patrizia Sciancalepore, Ezio Tripoli, Mario Boccadoro, and Massimo Massaia. "Immune Checkpoint Blockade Combinations As Promising Strategy for Cancer Immunotherapy in Multiple Myeloma Patients." Blood 128, no. 22 (December 2, 2016): 2059. http://dx.doi.org/10.1182/blood.v128.22.2059.2059.
Повний текст джерелаАнотація:
Abstract Tumor cells exploit immune checkpoints to withstand immune recognition and effector cells' onslaught. Pre-clinical findings, corroborated by initial results of clinical studies, indicate that immune checkpoint blockade is a promising strategy to harness anti-tumor immune responses and improve the clinical outcome of patients with hematological malignancies. Multiple myeloma (MM) is a prototypic disease in which immune checkpoints significantly contribute to the immune suppressive contexture that myeloma cells establish in the bone marrow (BM) in cooperation with regulatory T cells (Tregs), myeloid derived suppressor cells (MDSC), and BM stromal cells (BMSC). Vγ9Vδ2 T cells are among the immune effector cells strategically victimized by suppressor cells. These are non-conventional T cells halfway between innate and adaptive immunity with a natural inclination to react against malignant B cells, including myeloma cells. Vγ9Vδ2 T cells are equipped with a peculiar array of receptors for stress-induced self-ligands and a unique TCR-dependent recognition ability of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. Recently, we have shown that BM Vγ9Vδ2 T cells are anergic to pAg stimulation and that the programmed death 1(PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pair contributes to their dysfunction. This is an early event already detectable in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission after autologous stem cell transplantation (auto-SCT). Anti-PD-1 treatment partially recovers the ability of BM Vγ9Vδ2 T cells to proliferate and exert cytotoxic activity after pAg stimulation, but early studies based on single-agent PD-1 blockade have fallen short of clinical expectations in MM. Thus, several strategies are under consideration to implement the clinical efficacy of immune checkpoint blockade like the association with lenalidomide and/or concurrent tumor vaccination. Our results indicate that TIM-3 is significantly upregulated in BM Vγ9Vδ2 T cells from MM patients at diagnosis. We have previously shown that pAg stimulation of PD-1+ BM Vγ9Vδ2 T cells further increase PD-1 expression and preliminary data suggest that this stimulation also increases TIM-3 expression. Interestingly, TIM-3 up-regulation is even more pronounced than PD-1 up-regulation in BM Vγ9Vδ2 T cells and it occurs also in peripheral blood (PB) Vγ9Vδ2 T cells from anergic MM patients. We have recently shown that pAg reactivity of BM Vγ9Vδ2 T cells from MM at diagnosis can be partially recovered by PD-1 blockade. Our results reveal that TIM-3 blockade is also able to partially recover pAg-induced Vγ9Vδ2 T-cell proliferation. The best recovery is obtained when pAg stimulation is carried out in the presence of concurrent PD-1 and TIM-3 blockade. BM Vγ9Vδ2 T cells from MM patients who are in remission (MM-rem) after auto-SCT are still PD1+ and anergic to pAg stimulation. Remarkably, percentages of PD-L1+ MDSC in the BM of MM-rem are also unchanged compared to MM at diagnosis (MM-dia) and MM in relapse (MM-rel). These data indicate that the immune suppressive contexture is still operative at the tumor site even when most of myeloma cells have been cleared by chemotherapy. Interestingly, chemoresistant residual myeloma cells after auto-SCT have been reported to be PD-L1+, and circulating exhausted PD-1+ CD8+ T cells have been described in the PB after auto-SCT. This may explain why our previous idiotype vaccination studies in MM patients have failed. We have initiated to investigate the effect of immune checkpoint blockade in different phases of the disease and preliminary results suggest that the functional outcome of PD-1 blockade can be very different according to the disease status: the most signifcant recovery of Vγ9Vδ2 T-cell proliferation is observed after PD-1 blockade in MM-rem, while the anergy of Vγ9Vδ2 T cells from MM-rel is totally refractory to immune checkpoint blockade. In conclusion, our results suggest that recovery of pAg reactivity by PB Vγ9Vδ2 T cells is a reliable biomarker to predict or assess the clinical efficacy of immune checkpoint in vivo and provide scientific groundwork to optimize anti-PD1 treatment as single agent or in combination with other antibodies (i.e, anti-TIM-3) to maximize the efficacy of immune checkpoint blockade according to the disease status. Disclosures Boccadoro: Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Abbivie: Honoraria. Massaia:Roche: Other: advisory board, research support; Janssen: Other: advisory board; Gilead: Other: advisory board.
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Carvajal, Luis, Luciana Gneo, Carmela De Santo, Matt Perez, Tracy Garron, Francis Mussai та Annalisa D’Andrea. "473 Mavrilimumab, a human monoclonal antibody targeting GM-CSFRα, inhibits polarization to myeloid-derived suppressor cells (MDSCs) that express PD-L1 and restores T-cell proliferation in vitro". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (листопад 2020): A504. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0473.
Повний текст джерелаАнотація:
BackgroundMyeloid-derived suppressor cells (MDSCs) accumulate in the blood and tumor microenvironment (TME) and suppress anti-tumor immune responses.1 Cancer cells express the granulocyte-macrophage colony-stimulating factor (GM-CSF), which drives MDSC differentiation and function.2 3 4 It is upregulated in several cancers, including mesothelioma, pancreatic and colorectal, and it is linked to higher levels of intra-tumoral MDSCs and poorer overall survival.2 4 5 In animal models, knockdown of GM-CSF in pancreatic epithelium or pancreatic mesenchymal stem cells inhibits tumorigenesis, reduces intra-tumor MDSCs and enhances CD8+ T cell accumulation.6 7 8 Therefore, targeting the GM-CSF receptor alpha (GM-CSFRα) on MDSCs is an attractive strategy to restore anti-tumor immunity. Mavrilimumab is a clinical stage fully human monoclonal antibody that blocks GM-CSFRα. It has demonstrated efficacy and acceptable safety profile in patients with rheumatoid arthritis, and it’s currently undergoing investigation in phase II studies in giant cell arteritis and in patients with severe COVID-19 pneumonia and hyper-inflammation (NCT03827018, NCT04397497, respectively). The present study investigates its potential as a therapeutic strategy to target MDSCs in the TME as an adjuvant to immunotherapy.MethodsCancer cell supernatants were collected when cells reached confluency. Human GM-CSF was measured by ELISA. Healthy donor CD14+ monocytes were incubated (± mavrilimumab) with cancer cell supernatants for either 3 or 6 days followed by phenotypic analysis (CD14, CD33, HLA-DR, CD11b, CD206, CD80, PD-L1, Arginase-1) by flow cytometry. On day 3, autologous CD3+ T cells were stimulated with CD3/CD28 and IL-2 and co-cultured with putative MDSCs for 5 days. T-cell proliferation was evaluated by measuring carboxyfluorescein succinimidyl ester (CFSE) dilution in CD4+ and CD8+ T cells by flow cytometry.ResultsGM-CSF is expressed in the supernatant of cancer cell lines (HCT116, SW-480, Panc-1, Capan-1). Human monocytes cultured with conditioned medium from colorectal carcinoma (SW-480) or pancreatic adenocarcinoma (Capan-1) show downregulation of HLA-DR, increased expression of PD-L1, Arg-1, CD206, and can suppress T-cell proliferation in-vitro. Similarly, peripheral blood monocytes purified from pancreatic cancer patients suppress T-cell proliferation ex-vivo. Notably, Mavrilimumab inhibits the polarization of healthy donor monocytes to M-MDSCs and restores T-cell proliferation.ConclusionsTargeting of GM-CSFRα with mavrilimumab may alleviate the pro-tumorigenic and immunosuppressive functions of MDSCs in the TME. Future clinical studies should evaluate whether targeting of the GM-CSFRα in combination with immune checkpoint inhibitors is a viable therapeutic option to bolster their efficacy.Ethics ApprovalThe study was approved by the Institute of Immunology and Immunotherapy, University of Birmingham, UK Ethics Board. Healthy volunteer human material was obtained from commercial sources and approved by Stemexpress Institutional Review Board (IRB).ReferencesLaw AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells 2020;9(3):561.Khanna S, Graef S, Mussai F, et al. Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients. Clin Cancer Res 2018;24(12):2859–2872.Dolcetti L, Peranzoni E, Ugel S, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 2010;40(1):22–35.Takeuchi S, Baghdadi M, Tsuchikawa T, et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res 2015;75(13):2629–2640.Chen Y, Zhao Z, Chen Y, et al. An epithelial-to-mesenchymal transition-inducing potential of granulocyte macrophage colony-stimulating factor in colon cancer. Sci Rep 2017;7(1):8265.Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012;21(6):822–835.Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21(6):836–847.Waghray M, Yalamanchili M, Dziubinski M, et al. GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov 2016;6(8):886–899.
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Sanchez-Martin, Marta, Lei Wang, Jeffrey Ecsedy, Karen Mcgovern, and Michelle Zhang. "93 Computational biology and tissue-based approaches to inform indication selection for a novel AHR inhibitor." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A102. http://dx.doi.org/10.1136/jitc-2021-sitc2021.093.
Повний текст джерелаАнотація:
BackgroundAryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activities of multiple innate and adaptive immune cell types. Multiple ligands such as kynurenine bind to AHR driving its nuclear translocation and transcriptional activation, leading to an immunosuppressive tumor microenvironment.1 2 AHR activation is implicated in tumor development in multiple cancer types. In addition, high levels of serum kynurenine are associated with resistance to checkpoint inhibitors.3 To overcome AHR-mediated immunosuppression in cancers, we developed a selective oral AHR inhibitor IK-175 and took a combined computational and tissue-based approach to select cancer indications for its clinical development.MethodsThe aim of this work is to identify tumor indications dependent on AHR signaling and design patient selection strategies based on a proprietary transcriptional signature, mRNA and protein detection assays to evaluate AHR pathway activation in tumors.ResultsGenomic profiling of solid and hematological cancers from TCGA and Project GENIE databases identified bladder and esophageal tumors among others, as frequently harboring AHR gene amplifications.A proprietary gene signature of AHR activation was developed integrating literature, pathway analysis, RNAseq and nanostring data from PBMC, T-cells and cell lines upon AHR inhibition. Transcriptional analysis of the TCGA data using this signature demonstrated bladder cancer has the highest expressions of AHR and AHR signature genes, suggesting increased pathway activity in bladder cancer relative to other cancer types. Increased AHR signature gene expression was associated with worse overall survival in the TCGA bladder cancer cohort. Furthermore, RNAscope analysis of a tissue microarray containing 10 different tumor types revealed bladder cancer had one of the highest AHR transcript expression in the tumor compartment.Finally, nuclear localization of AHR protein was assessed as an indicator of pathway activation through the development of a novel IHC method. Extensive TMA screening of AHR protein in 15 different indications demonstrated bladder cancer as the tumor type with the highest prevalence of AHR nuclear expression.ConclusionsIn summary, we demonstrated high prevalence of nuclear AHR protein expression, AHR gene amplification and target gene expression in bladder cancer, suggesting aberrant AHR activation may play an important role in the progression of this tumor type. This study provides rationale for therapeutic targeting of AHR in bladder cancer patients. Ikena is currently evaluating the anti-tumor activity of IK-175 as a single agent and in combination with nivolumab in bladder cancer in a Phase 1a/1b clinical study (NCT04200963).ReferencesQuintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013 Aug 1;65(4):1148–61.Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014 Dec;14(12):801–14.Li, Haoxin et al. ‘Metabolomic adaptations and correlates of survival to immune checkpoint blockade.’ Nature Communications 2019 Sep 25;10:1–4346.
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Papadas, Athanasios, Gauri Deb, Adam Officer, Chelsea Hope, Philip Emmerich, Alexander Cicala, Joshua Wiesner, et al. "936 Stromal remodeling regulates dendritic cell abundance in the tumor microenvironment." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A982. http://dx.doi.org/10.1136/jitc-2021-sitc2021.936.
Повний текст джерелаАнотація:
BackgroundStimulatory dendritic cells (SDC), enriched within the Batf3-DC lineage (also known as conventional type 1 DC, cDC1), engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. This puzzling pattern of T-cell-DC localization has been interpreted as ”tumor-exclusion”, limiting anti-tumor immunity. To understand this paradox, we hypothesized that dynamic matrix remodeling at the invasive margin generates unique activation and cell-fate cues critical for Batf3-DC homeostasis.MethodsWe studied immunocompetent tumor models of lung carcinoma, breast carcinoma, melanoma and multiple myeloma. For mechanistic experiments, we generated novel Vcan-targeted models through CRISPR-Cas9 targeting. We delineated DC subsets through multi-parametric flow cytometry and tumor immune contexture through mass cytometry. Batf3-DC cellular models included MutuDC1940 immortalized DC and iCD103 primary cells. TCGA data were mined for human validation.ResultsWe find that CD8+ T cells massively infiltrate tumor matrices undergoing robust matrix proteoglycan versican (VCAN) proteolysis, an essential organ-sculpting modification in development and adult tissue-plane forging. Across 7591 samples from 20 TCGA cancer types, a significant-positive correlation between VCAN substrate expression and Batf3-DC score was observed, suggesting that the VCAN pathway may regulate Batf3-DC across several cancer types. Experimental Vcan depletion in the tumor microenvironment was detrimental for Batf3-DC. Batf3-DC abundance was restored through the VCAN N-terminal fragment (matrikine) versikine, physiologically generated through ADAMTS protease activity in remodeled stroma. In addition to Batf3-DC expansion, versikine resulted in G-MDSC contraction as well as the emergence of an atypical innate lymphoid (NK/ILC1) subset expressing cytotoxicity receptors, low IFNgamma and robust pro-survival GM-CSF. Despite broad intratumoral IRF8 induction (10-100-fold), adoptive transfer of pre-DC into versikine-replete microenvironments did not influence their differentiation choice between Batf3-DC and cDC2. Instead, versikine delivered a distinct Batf3-DC activation signal characterized by non-TLR maturation as well as downregulation of TGFbeta and Wnt signaling. In vivo, versikine promoted Batf3-DC abundance through NK cells but independently of stromal TLR2 or CD44. Versikine sensitized immune-evasive tumors to STING agonist immunotherapy in a Batf3-DC dependent manner and promoted antigen-specific CD8+ responses. Versikine-DC signatures correlated with CD8+ T cell scores in human lung cancers.ConclusionsWe demonstrate that dynamic extracellular matrix remodeling controls Batf3-DC abundance in the tumor microenvironment. N-terminal proteolysis of the matrix proteoglycan versican (VCAN), releases a bioactive fragment (matrikine), versikine, that is remarkably necessary and sufficient for Batf3-DC accumulation. Versikine orchestrates a multi-lineage network that regulates Batf3-DC activation and survival at matrix-remodeling interfaces. Therapeutic harnessing of matrix-Batf3-DC cross-talk sensitizes immune-evasive tumors to immunotherapy.AcknowledgementsWe acknowledge support by the National Cancer Institute (R01CA252937 and U01CA196406), the American Cancer Society (127508-RSG-15-045-01-LIB), the Leukemia and Lymphoma Society (6551–18), the UW Trillium Myeloma Fund and the Robert J. Shillman Foundation.Ethics ApprovalLaboratory animal work was performed under IACUC-approved protocols #M5476 and #S19109 in the University of Wisconsin-Madison and University of California, San Diego respectively.