Academic literature on the topic 'MDSC, CANCER IMMUNOLOGY, IMMUNOSUPPRESSION, INNATE IMMUNITY'

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.

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

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)

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.

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.

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.

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.

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.

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.

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.

During tumor progression, cancer cells secrete many different tumor-derived factors (TDFs), like cytokines, chemokines, and metabolites, which promote the development of a flexible microenvironment inducing bot the generation of new vessels and the modification of the immune responses (Balkwill, Charles et al. 2005). Probably the most pervasive and efficient strategy of “tumor escape” relies on the tumor’s ability to create a tolerant microenvironment by modification of the normal hematopoiesis. Indeed, cancers can induce the proliferation and differentiation of myeloid precursors into myeloid cells with immunosuppressive functions. These cells, named myeloid-derive suppressor cells (MDSCs), are a heterogeneous population of myeloid cells emcompassing various stages of differentiation. MDSCs prevent the activation and functionality of T lymphocytes, limiting the success of immunotherapy strategies aimed at eradicating cancer development. In this study, we demonstrated that low dose of chemotherapeutics with different molecular targets and cytotoxic action, widely used in conventional anti-cancer therapy, were able to selectively deplete monocytic-MDSCs (M-MDSCs), restoring the T cell proliferation. We also proved that these drugs exert their action through the activation of the apoptotic death pathway and with the specific modulation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP), a well-known anti-apoptotic and drug resistance factor. In particular, recent study in mice demonstrated that the heterogeneity between the two main subsets of MDSCs, the M-MDSCs and the polymorphonuclear/granulocytic (PMN)-MDSCs, occurs from a diverse activation of the apoptotic pathways: PMN-MDSCs require the anti-apoptotic molecule MCL-1 for their development; in contrast, M-MDSC generation and survival constitutively requires the presence of c-FLIP (Haverkamp, Smith et al. 2014). Therefore, in this study we verified and demonstrated the hypothesis that c-FLIP can have also a role in driving and controlling MDSC immunosuppressive properties.

An understanding of the main aspects and functions of the immune system is important, i.e. physical barriers, innate, humoral, and cell-mediated immunity (see Chapter 6, Basic Immunology), when caring for the immunocompromised patient. In adults, secondary immunodeficiency is much more common than primary, and is most often due to iatrogenic immunosuppression with drugs, e.g. corticosteroids, chemotherapy agents, immunosuppressive agents, ‘biological’ therapies. For example, treatment with corticosteroids for more than one month is enough to increase the risk of some fungal infections such as Candida and Pneumocystis jirovecii, such that PCP prophylaxis should be considered in patients receiving ≤ 20mg/day prednisolone for four or more weeks. Chemotherapy and immunosuppressive agents may cause profound immunosuppression. The degree and duration of immunosuppression following a transplant, and the conditioning regimen used before the transplant varies with respect to the type of transplant: heart and lung transplant recipients typically receive more significant immunosuppression, and so are at increased risk of opportunistic infection compared to other solid-organ transplant recipients. Infections (e.g. HIV), cancer, and autoimmune disorders and the treatment of these conditions can also affect the immune system. Other diseases are also considered immunosuppressive although the exact nature of this is less well defined, for example, poorly controlled diabetes mellitus increases the risk of candidal infections and common bacterial infections. Cirrhosis is also considered to be a relatively immunosuppressed state. Understanding the nature of immune defects in both primary and secondary immunodeficiency allows more accurate prediction of overall infection risk and risk of specific pathogens, allowing a rational approach to infection prevention and investigation when patients become unwell. The initial assessment of the immunocompromised host should be to identify why the patient is immunocompromised, how long they have been immunocompromised (is it a congenital or acquired immunodeficiency?), and whether there is potential for immune recovery. Clearly, a person with a congenital immunodeficiency will have lifelong susceptibility to specific infections, unlike an acquired deficiency due to chemotherapy or transplantation which may be transient. If the immunosuppression is due to a drug, is it possible to reduce or change the immunosuppression? If an infection is suspected, pre-immunosuppression infection screening results can help identify whether the current presentation represents reactivation of a latent infection or primary infection.