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Riachi, Mansour E., Carolina G. Alcantara Hirsch, Erica Ma, Beny Shapiro, Ammar Javed, Christopher L. Wolfgang, and Dafna Bar-Sagi. "Abstract A018: Exercise stimulates anti-tumoral immunity in metastatic PDAC." Cancer Research 84, no. 2_Supplement (January 16, 2024): A018. http://dx.doi.org/10.1158/1538-7445.panca2023-a018.
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Abstract The majority of pancreatic ductal adenocarcinoma (PDAC) patients are metastatic at presentation with limited treatment options and a poor overall 5-year survival of 3%. The liver is the predominant site of distant metastasis in PDAC. Our group has previously shown that aerobic exercise can inhibit tumorigenesis in a primary PDAC mouse model by promoting anti-tumor immunity, however, the effects of exercise in the metastatic setting have not been explored. As such, we developed a model of PDAC liver metastasis by isolating primary pancreatic and liver metastatic cell lines from 18–20-week-old LSL-KRasG12D/+; LSL-Trp53R172H/+; p48Cre; Rosa26LSL-tdTomato/+ (KPCTpancreas or KPCTliver, respectively) mice. KPCTpancreas cells were surgically implanted into the pancreata of syngeneic wild-type mice. One week after pancreatic implantation, KPCTliver cells were implanted into the liver either by direct injection into the parenchyma or via the portal vein. The portal vein method enables us to account for the extravasation step of the metastatic cascade, while the direct parenchymal injection offers a less invasive surgery. Both models preserve the spleen, which is the largest secondary lymphoid organ and essential to the immune response. Treadmill running was initiated in the aerobic exercise cohort 5 days per week for 2 weeks or mice were allowed to rest. Endpoint analysis revealed that aerobic exercise treatment decreased tumor burden in both primary tumors and liver metastasis as measured by tumor weights and tdTomato fluorescence imaging when compared to the rested controls. Immune profiling of the liver metastases revealed elevated IL-15Rɑ+ CD8+ T cells as well as CD19+ B cells in the exercise cohort. While identification of IL-15Rɑ+ CD8+ T cells is consistent with the immune changes we have previously reported in the primary pancreatic tumor of exercised mice, the latter changes reveal organ specific immune cell recruitment not observed in the primary pancreatic tumor of exercised mice. The combined immune profiling and phenotypic changes suggest that aerobic exercise reduces PDAC metastatic growth by modulating systemic and intra-tumoral immunity. The induction of an anti-tumorigenic immune response by aerobic exercise could open avenues for potential pharmacological intervention in downstream pathways to aid in the treatment of metastatic PDAC. Citation Format: Mansour E. Riachi, Carolina G. Alcantara Hirsch, Erica Ma, Beny Shapiro, Ammar Javed, Christopher L. Wolfgang, Dafna Bar-Sagi. Exercise stimulates anti-tumoral immunity in metastatic PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A018.
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Bikorimana, Jean-Pierre, Natasha Salame, Simon Beaudoin, Mohammad Balood, Théo Crosson, Jamilah Abusarah, Sebastien Talbot, Raimar Löbenberg, Sebastien Plouffe, and Moutih Rafei. "Promoting antigen escape from dendritic cell endosomes potentiates anti-tumoral immunity." Cell Reports Medicine 3, no. 3 (March 2022): 100534. http://dx.doi.org/10.1016/j.xcrm.2022.100534.
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Leshem, Yasmin, Emily King, Ronit Mazor, Yoram Reiter, and Ira Pastan. "SS1P Immunotoxin Induces Markers of Immunogenic Cell Death and Enhances the Effect of the CTLA-4 Blockade in AE17M Mouse Mesothelioma Tumors." Toxins 10, no. 11 (November 14, 2018): 470. http://dx.doi.org/10.3390/toxins10110470.
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SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced. The goal of this study is to evaluate if SS1P therapy renders mesothelioma tumors more sensitive to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade. We evaluated the ability of SS1P to induce adenosine triphosphate (ATP) secretion and calreticulin expression on the surface of AE17M mouse mesothelioma cells. Both properties are associated with immunogenic cell death. Furthermore, we treated these tumors with intra-tumoral SS1P and systemic CTLA-4. We found that SS1P increased the release of ATP from AE17M cells in a dose and time-dependent manner. In addition, SS1P induced calreticulin expression on the surface of AE17M cells. These results suggest that SS1P promotes immunogenic cell death and could sensitize tumors to anti-CTLA-4 based therapy. In mouse studies, we found that the combination of anti-CTLA-4 with intra-tumoral SS1P induced complete regressions in most mice and provided a statistically significant survival benefit compared to monotherapy. The surviving mice were protected from tumor re-challenge, indicating the development of anti-tumor immunity. These findings support the use of intra-tumoral SS1P in combination with anti-CTLA-4.
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Giurini, Eileena F., Mary Beth Madonna, Andrew Zloza, and Kajal H. Gupta. "Microbial-Derived Toll-like Receptor Agonism in Cancer Treatment and Progression." Cancers 14, no. 12 (June 14, 2022): 2923. http://dx.doi.org/10.3390/cancers14122923.
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Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first discovery of the Toll receptor by the team of J. Hoffmann in 1996, in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. TLR stimulation leads to NF-κB activation and the subsequent production of pro-inflammatory cytokines and chemokines, growth factors and anti-apoptotic proteins. The expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. The anti-tumoral effects can result from the activation of anti-tumoral immune responses and/or the direct induction of tumor cell death. The pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment. The aim of this review is to draw attention to the effects of TLR stimulation in cancer, the activation of various TLRs by microbes in different types of tumors, and, finally, the role of TLRs in anti-cancer immunity and tumor rejection.
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Rivera-Molina, Yisel, Juan Fueyo, Hong Jiang, Teresa Nguyen, Dong Ho Shin, Gilbert Youssef, Xuejun Fan, et al. "EXTH-27. ACTIVATING THE IMMUNITY WITHIN THE TUMOR USING VIROIMMUNOTHERAPY: DELTA-24-RGD ONCOLYTIC ADENOVIRUS ARMED WITH THE IMMUNOPOSITIVE REGULATOR GITRL." Neuro-Oncology 21, Supplement_6 (November 2019): vi87. http://dx.doi.org/10.1093/neuonc/noz175.359.
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Abstract Based on promising results of recent clinical trials using oncolytic viruses, virotherapy is evolving as an alternative to treat patients with malignant glioma. Our group developed the oncolytic adenovirus Delta-24-RGD (DNX-2401) that is being tested, alone or in combination with anti-PD1, in clinical trials for recurrent glioblastoma (NCT00805376; NCT01956734; NCT02798406). The results suggest that, besides the expected oncolytic effect, the injection of the pathogen initiated, in a subset of patients, an anti-tumoral immunity that led to 20% of long-term survivors (3.5–5 years). To further enhance this effect, we have armed Delta-24-RGD to express the co-stimulatory ligand GITRL, and generated Delta-24-GREAT. The intracranial injection of Delta-24-GREAT prolonged the survival of GL261 glioma-bearing immunocompetent mice when compared to Delta-24-RGD treatment (P=0.002, log-rank test). Delta-24-GREAT treatment resulted in enhanced frequency of tumor-infiltrating lymphocytes: T lymphocytes (CD45+/CD3+) and cytotoxic T lymphocytes (CD45+CD3+CD8+). Functional studies performed by culturing splenocytes from Delta-24-GREAT-treated mice with glioma cells and analyzing secretion of Th1 cytokines, such as IL2 and IFN-γ, showed that lymphocytes recognized not only viral antigens but also tumoral antigens, suggesting the triggering of anti-tumoral immunity. Of interest, Delta-24-GREAT treatment resulted in an antigen-restricted anti-tumor memory effect and in the generation of central immune memory. Thus, rechallenging the survivor mice from the first experiment with a second implantation of glioma cells did not lead to tumor growth, and we detected an increased frequency of central memory CD8+ T cells (CD45+CD62L+). However, survivor mice developed lethal tumors when implanted intracranially with B16/F10 melanoma cells, strongly indicating that the developed immune response was specific for GL261 glioma antigens. This is a novel approach using an oncolytic adenovirus expressing GITRL to target cancer and to stimulate the immunity within the tumor. Our data strongly indicate that this type of strategy may be further developed to treat patients with malignant glioblastoma.
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Cohen-Solal, Joel F. G., Lydie Cassard, Emilie M. Fournier, Shannon M. Loncar, Wolf Herman Fridman, and Catherine Sautès-Fridman. "Metastatic Melanomas Express Inhibitory Low Affinity Fc Gamma Receptor and Escape Humoral Immunity." Dermatology Research and Practice 2010 (2010): 1–11. http://dx.doi.org/10.1155/2010/657406.
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Our research, inspired by the pioneering works of Isaac Witz in the 1980s, established that 40% of human metastatic melanomas express ectopically inhibitory Fc gamma receptors (FcRIIB), while they are detected on less than 5% of primary cutaneous melanoma and not on melanocytes. We demonstrated that these tumoral FcRIIB act as decoy receptors that bind the Fc portion of antimelanoma IgG, which may prevent Fc recognition by the effector cells of the immune system and allow the metastatic melanoma to escape the humoral/natural immune response. The FcRIIB is able to inhibit the ADCC (antibody dependent cell cytotoxicity) in vitro. Interestingly, the percentage of melanoma expressing the FcRIIB is high (70%) in organs like the liver, which is rich in patrolling NK (natural killer) cells that exercise their antitumoral activity by ADCC. We found that this tumoral FcRIIB is fully functional and that its inhibitory potential can be triggered depending on the specificity of the anti-tumor antibody with which it interacts. Together these observations elucidate how metastatic melanomas interact with and potentially evade humoral immunity and provide direction for the improvement of anti-melanoma monoclonal antibody therapy.
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Mirlekar, Bhalchandra, and Yuliya Pylayeva-Gupta. "Abstract PO-019: Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—019—PO—019. http://dx.doi.org/10.1158/1538-7445.panca21-po-019.
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Abstract B cells frequently infiltrate human tumors, and the intra-tumoral abundance of plasma cells can correlate with improved patient prognosis. However, many tumors are devoid of plasma B cells, and strategies to enhance anti-tumor B cell responses are needed. We report the existence of a negative regulatory signaling network that reprograms naïve B cells in pancreatic cancer to antagonize anti-tumor plasma B cells. This network is driven by IL-35-mediated STAT3 activation, which directly stimulates upregulation of the pioneer transcription factors Pax5 and Bcl6 in naïve B cells and impedes plasma cell differentiation while simultaneously activating regulatory B cell phenotypes. Significantly, inhibition of Bcl6 reversed this tumor-associated reprogramming of naïve B cells, enabling intra-tumoral accumulation of plasma cells, and reduced tumor growth. Our data provide evidence that B cell dysfunction in cancer involves a potentially targetable suppression program that alters the differentiation potential of naïve B cells. Citation Format: Bhalchandra Mirlekar, Yuliya Pylayeva-Gupta. Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-019.
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Geidel, G., M. Maurer, T. Luger, and K. Loser. "649 OX40/OX40L and 4-1BB/4-1BBL signaling in cutaneous anti-tumoral immunity." Journal of Investigative Dermatology 136, no. 5 (May 2016): S115. http://dx.doi.org/10.1016/j.jid.2016.02.690.
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Wu, Deyang, Xiaowei Liu, Jingtian Mu, Jin Yang, Fanglong Wu, and Hongmei Zhou. "Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers." Biomolecules 12, no. 3 (March 2, 2022): 392. http://dx.doi.org/10.3390/biom12030392.
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Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical protein markers, while simultaneously having unique transcriptional features, which makes the proteins expressed on TAMs promising targets during anti-tumor therapy. Herein, TAM-associated protein-dependent target strategies were developed with the aim of either reducing the numbers of TAMs or inhibiting the pro-tumoral functions of TAMs. Furthermore, the recent advances in TAMs associated with tumor metabolism and immunity were extensively exploited to repolarize these TAMs to become anti-tumor elements and reverse the immunosuppressive tumor microenvironment. In this review, we systematically summarize these current studies to fully illustrate the TAM-associated protein targets and their inhibitors, and we highlight the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-tumor therapy.
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Remsik, Jan, Xinran Tong, Min Jun Li, Ugur Sener, Jessica Wilcox, Kiana Chabot, Russell Kunes, et al. "LMD-16. Choroid plexus orchestrates anti-cancer immunity in leptomeninges." Neuro-Oncology Advances 3, Supplement_3 (August 1, 2021): iii10—iii11. http://dx.doi.org/10.1093/noajnl/vdab071.041.
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Abstract Choroid plexus (CP) forms an anatomically functional barrier between the blood and cerebrospinal fluid (CSF) that dictates the cellular and humoral composition of the CSF. The immunological response of CP to inflammatory stimuli, such as cancer, remains unclear. Here, we find that CP orchestrates the immune composition of CSF in the steady state as well as in the presence of metastatic cancer. We show that the circulation-derived leptomeningeal monocyte-macrophages entering the CSF through CP promote the growth of leptomeningeal metastasis (LM) by perturbing the environment with a storm of dozens of pro- and anti-inflammatory cytokines. Functional manipulation of Type II Interferon pathway specifically within inflamed leptomeninges revealed that IFN-γ can serve as a dominant signal, further recruiting peripheral myeloid cells and activating their protective anti-tumoral response. This preclinical strategy was sufficient to controll the growth of syngeneic LM cancer cells and delay the onset of lethal LM.
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Revel, Margot, Marie V. Daugan, Catherine Sautés-Fridman, Wolf H. Fridman, and Lubka T. Roumenina. "Complement System: Promoter or Suppressor of Cancer Progression?" Antibodies 9, no. 4 (October 25, 2020): 57. http://dx.doi.org/10.3390/antib9040057.
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Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.
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Lee, Eun Jung, Da Hyeon Yun, Seungpil Jung, and Serk In Park. "Abstract 2191: Alteration of anti-tumoral immunity in the pre-metastatic bone microenvironment via autonomic nerve system dysfunction." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2191. http://dx.doi.org/10.1158/1538-7445.am2022-2191.
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Abstract Bone metastasis is a major cause of morbidity and mortality for breast cancer patients. Bone is a unique metastatic microenvironment because of complex interactions among numerous distinct cell types such as osteo-blasts, -clasts, -cytes and marrow immune cells in physiological and pathological conditions. Imbalanced bone homeostasis by diverse factors such as the sympathetic nerve system (SNS) activation, potentially contribute to the progression of bone metastasis, yet precise mechanisms remain unclear. We investigated the effects of beta 2 adrenergic receptor (β2AR) activation in osteoblasts induced by prolonged SNS stimulation on anti-tumoral immunity in bone metastasis. We treated female Balb/C with chronic immobilization stress (CIS; 2 h. daily) and found that CIS increased syngeneic intra-tibial 4T1 bone metastasis growth as well as the number of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) counterbalancing anti-tumoral cytotoxic T cells in bone microenvironment. A β2AR-specific inhibitor (ICI-118551) or MDSC depletion using anti-Gr1 antibodies reversed CIS-induced bone metastatic tumor growth. More importantly, 2-week CIS pre-treatment increased EDU+ MDSC proliferation in the bone marrow, contributing to subsequent bone metastatic tumor growth and micro-metastatic seeding in intra-tibial and intra-cardiac tumor injection models, respectively. When CIS was administered after the establishment of bone metastatic tumors, the pro-tumorigenic effects were marginal. In osteoblast-specific β2AR knockout mice (Adrb2flox/flox; murine 2.3kb Col1-CreC57BL6 mice), CIS did not increase MDSC proliferation compared with littermate floxed controls, suggesting that β2AR in osteoblasts upregulates MDSC in bone microenvironment. RNA-sequencing transcriptome analysis of saline- or clenbuterol (a selective β2AR agonist)-treated murine osteoblasts showed that interleukin-6 (IL6) was the most significantly increased cytokine. Indeed, CIS or clenbuterol treatment increased IL-6 expression in vivo (immunohistochemistry) and in vitro (cultured osteoblasts), respectively. MDSC isolated from the bone marrow of CIS-treated mice had significantly increased STAT3 phosphorylation by flow cytometry and the expression of immuno-suppressive functional molecules such as arginase 1 (Arg1) and indolamine 2,3-dioxygenase 1 (Ido1) compared to those from control mice. Our data collectively demonstrated that SNS-dependent β2AR in osteoblasts expands and activates MDSC in the pre-metastatic bone microenvironment via the IL6-STAT3-Arg1/IDO1 pathway, creating a fertile soil for bone metastasis progression. Our data provided the first direct evidence for anti-tumoral immunity and pro-tumorigenic effects of autonomous nerve system dysfunction specific to the metastatic bone microenvironment. Citation Format: Eun Jung Lee, Da Hyeon Yun, Seungpil Jung, Serk In Park. Alteration of anti-tumoral immunity in the pre-metastatic bone microenvironment via autonomic nerve system dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2191.
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Wang, Xuefeng, Xin Gao, Xin Zhao, Qianting Yang, Yuan Qi, Shayang Zang, Xueguang Zhang, and Binfeng Lu. "Tumoral expression of IL-33 promotes Anti-tumor Immune Responses (TUM2P.912)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 71.36. http://dx.doi.org/10.4049/jimmunol.192.supp.71.36.
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Abstract One major approach of cancer immune therapy is to convert the tumor immunosuppressive microenvironment to one that favors antitumor immune responses. We have recently demonstrated that Interleukin 33 (IL-33) promotes effector functions of CD8 T cells, suggesting a potential function in antitumor immunity. Here we showed that overexpression of IL-33 in two tumor cell lines, 4T1 and B16, potently inhibited tumor growth in vivo. CD45+, CD8+ T cells, NK cells, IFN-γ+ CD8+ T cells and IFN-γ+ NK cells were greatly increased in the IL-33-expressing tumors when compared with those in the control tumors. We further demonstrated that the antitumor effect of IL-33 was dependent on NK cells and CD8 T cells. In contrast, MDSC were greatly decreased in the IL-33-expressing tumors when compared to those in the control tumors. Our results indicate that the intratumoral delivery of IL-33 can be a new strategy of tumor immunotherapy by promoting an immunogenic microenvironment.
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Brummer, Christina, Tobias Pukrop, Joachim Wiskemann, Christina Bruss, Ines Ugele, and Kathrin Renner. "Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?" Cancers 15, no. 18 (September 21, 2023): 4668. http://dx.doi.org/10.3390/cancers15184668.
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Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance.
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Zerdes, Wallerius, Sifakis, Wallmann, Betts, Bartish, Tsesmetzis, et al. "STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer." Cancers 11, no. 10 (October 1, 2019): 1479. http://dx.doi.org/10.3390/cancers11101479.
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Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and anti-tumor responses were investigated in breast cancer (BC). A transcriptional signature of phosphorylated STAT3 was positively correlated with PD-L1 expression in two independent cohorts of early BC. Pharmacologic inhibition and gene silencing of STAT3 led to decreased Programmed Death Ligand 1 (PD-L1) expression levels in vitro, and resulted as well in reduction of tumor growth and decreased metastatic dissemination in a mammary carcinoma mouse model. The hampering of tumor progression was correlated to an anti-tumoral macrophage phenotype and accumulation of natural-killer cells, but also in reduced accrual of cytotoxic lymphocytes. In human BC, pro-tumoral macrophages correlated to PD-L1 expression, proliferation status and higher grade of malignancy, indicating a subset of patients with immunosuppressive properties. In conclusion, this study provides evidence for STAT3-mediated regulation of PD-L1 and modulation of immune microenvironment in BC.
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Rosato, Pamela, Jianfang Ning, Noah Veis Gavil, Shaoping Wu, Sathi Wijeyesinghe, Eyob Weyu, Jun Ma, et al. "Functional virus-specific memory CD8+ T cells survey glioblastoma." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 121.15. http://dx.doi.org/10.4049/jimmunol.208.supp.121.15.
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Abstract Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host, including the brain, and are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific memory T cells through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific memory T cells are a significant part of the glioblastoma immune microenvironment and may be leveraged to promote anti-tumoral immunity. Supported by UMN SPORE Program Project Planning grant (DM, CCC), NCI 1R01CA238439 (DM), Humor to Fight the Tumor Foundation (JN), NCI 5P30CA023108-42 (PR)
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Kendal, Joseph K., Michael S. Shehata, Serena Y. Lofftus, and Joseph G. Crompton. "Cancer-Associated B Cells in Sarcoma." Cancers 15, no. 3 (January 19, 2023): 622. http://dx.doi.org/10.3390/cancers15030622.
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Despite being one of the first types of cancers studied that hinted at a major role of the immune system in pro- and anti-tumor biology, little is known about the immune microenvironment in sarcoma. Few types of sarcoma have shown major responses to immunotherapy, and its rarity and heterogeneity makes it challenging to study. With limited systemic treatment options, further understanding of the underlying mechanisms in sarcoma immunity may prove crucial in advancing sarcoma care. While great strides have been made in the field of immunotherapy over the last few decades, most of these efforts have focused on harnessing the T cell response, with little attention on the role B cells may play in the tumor microenvironment. A growing body of evidence suggests that B cells have both pro- and anti-tumoral effects in a large variety of cancers, and in the age of bioinformatics and multi-omic analysis, the complexity of the humoral response is just being appreciated. This review explores what is currently known about the role of B cells in sarcoma, including understanding the various B cell populations associated with sarcoma, the organization of intra-tumoral B cells in tertiary lymphoid structures, recent trials in immunotherapy in sarcoma, intra-tumoral immunoglobulin, the pro-tumor effects of B cells, and exciting future areas for research.
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Veneziani, Irene, Claudia Alicata, Lorenzo Moretta, and Enrico Maggi. "The Latest Approach of Immunotherapy with Endosomal TLR Agonists Improving NK Cell Function: An Overview." Biomedicines 11, no. 1 (December 27, 2022): 64. http://dx.doi.org/10.3390/biomedicines11010064.
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Toll-like receptors (TLRs) are the most well-defined pattern recognition receptors (PRR) of several cell types recognizing pathogens and triggering innate immunity. TLRs are also expressed on tumor cells and tumor microenvironment (TME) cells, including natural killer (NK) cells. Cell surface TLRs primarily recognize extracellular ligands from bacteria and fungi, while endosomal TLRs recognize microbial DNA or RNA. TLR engagement activates intracellular pathways leading to the activation of transcription factors regulating gene expression of several inflammatory molecules. Endosomal TLR agonists may be considered as new immunotherapeutic adjuvants for dendritic cell (DC) vaccines able to improve anti-tumor immunity and cancer patient outcomes. The literature suggests that endosomal TLR agonists modify TME on murine models and human cancer (clinical trials), providing evidence that locally infused endosomal TLR agonists may delay tumor growth and induce tumor regression. Recently, our group demonstrated that CD56bright NK cell subset is selectively responsive to TLR8 engagement. Thus, TLR8 agonists (loaded or not to nanoparticles or other carriers) can be considered a novel strategy able to promote anti-tumor immunity. TLR8 agonists can be used to activate and expand in vitro circulating or intra-tumoral NK cells to be adoptively transferred into patients.
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Araújo, Thaise Gonçalves, Sara Teixeira Soares Mota, Helen Soares Valença Ferreira, Matheus Alves Ribeiro, Luiz Ricardo Goulart, and Lara Vecchi. "Annexin A1 as a Regulator of Immune Response in Cancer." Cells 10, no. 9 (August 30, 2021): 2245. http://dx.doi.org/10.3390/cells10092245.
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Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the N-terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor.
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Kim, Do-Hyun, Sangho Lim, Hong-Gyun Lee, Chun Geun Lee, Jack A. Elias, and Je-Min Choi. "Regulation of Chitinase-3-like-1 in T cell enhances anti-tumoral T cell responses to suppress lung metastasis." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 57.27. http://dx.doi.org/10.4049/jimmunol.200.supp.57.27.
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Abstract Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we showed that Chi3l1 expression was increased in Th2 cells while it decreased in Th1 cells by time dependent manner. In addition, Chi3l1-deficient T cells were hyper-responsive to TcR stimulation and were prone to differentiating into Th1 cells, and retroviral transduction of Chi3l1 rescue increased IFNγ expression in Chi3l1-deficient Th1 cells. Chi3l1-deficient Th1 cells showed increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice showed reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, knockdown of Chi3l1 expression in the lung using peptide-siRNA complex efficiently inhibited lung metastasis with enhanced Th1 and CTL infiltration and functions. Collectively, this study demonstrates Chi3l1 is a novel regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity.
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Trandafir, Maria-Florina, Octavian Savu, Daniela Pasarica, Coralia Bleotu, and Mihaela Gheorghiu. "Interleukin-6 as a Director of Immunological Events and Tissue Regenerative Capacity in Hemodialyzed Diabetes Patients." Medical Sciences 12, no. 2 (June 15, 2024): 31. http://dx.doi.org/10.3390/medsci12020031.
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Hemodialyzed patients have innate immunity activation and adaptive immunity senescence. Diabetes mellitus is a frequent cause for chronic kidney disease and systemic inflammation. We studied the immunological pattern (innate and acquired immunity) and the tissular regeneration capacity in two groups of hemodialyzed patients: one comprised of diabetics and the other of non-diabetics. For inflammation, the following serum markers were determined: interleukin 6 (IL-6), interleukin 1β (IL-1β), tumoral necrosis factor α (TNF-α), IL-6 soluble receptor (sIL-6R), NGAL (human neutrophil gelatinase-associated lipocalin), and interleukin 10 (IL-10). Serum tumoral necrosis factor β (TNF-β) was determined as a cellular immune response marker. Tissue regeneration capacity was studied using neurotrophin-3 (NT-3) and vascular endothelial growth factor β (VEGF-β) serum levels. The results showed important IL-6 and sIL-6R increases in both groups, especially in the diabetic patient group. IL-6 generates trans-signaling at the cellular level through sIL-6R, with proinflammatory and anti-regenerative effects, confirmed through a significant reduction in NT-3 and VEGF-β. Our results suggest that the high serum level of IL-6 significantly influences IL-1β, TNF-β, NT-3, VEGF-β, and IL-10 behavior. Our study is the first that we know of that investigates NT-3 in this patient category. Moreover, we investigated VEGF-β and TNF-β serum behavior, whereas most of the existing data cover only VEGF-α and TNF-α in hemodialyzed patients.
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Qiao, Rong, Rong Xiao, Zhong Chen, Jingwei Jiang, Chenghua Yuan, Shuxiang Ning, Jihong Wang, and Zunchun Zhou. "Cloning, Expression and Inhibitory Effects on Lewis Lung Carcinoma Cells of rAj-Tspin from Sea Cucumber (Apostichopus japonicus)." Molecules 27, no. 1 (December 30, 2021): 229. http://dx.doi.org/10.3390/molecules27010229.
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In recent years, sea cucumber has become a favorite healthcare food due to its characteristic prevention of cardiovascular diseases, suppression of tumors, as well as enhancement of immunity. In order to screen the anti-tumoral proteins or peptides from sea cucumber (Apostichopus japonicus), its cDNA library was analyzed, and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13)-like was found. ADAMTS13-like contains 10 thrombospondin 1 (TSP1) domains. Based on analysis of bioinformatics, the third TSP1 domain of this protein, which is further named Aj-Tspin, contains an arginine-glycine-aspartate (RGD) motif. Since our previous studies showed that the recombinant RGD-containing peptide from lampreys showed anti-tumoral activity, the third TSP1 domain of ADAMTS13-like was chosen to evaluate it’s effect on tumor proliferation and metastasis, despite the fact it shares almost no homologue with disintegrins from other species. After artificial synthesis, its cDNA sequence, Aj-Tspin, which is composed of 56 amino acids, was subcloned into a pET23b vector and expressed as a recombinant Aj-Tspin (rAj-Tspin) in a soluble form with a molecular weight of 6.976 kDa. Through affinity chromatography, rAj-Tspin was purified as a single protein. Both anti-proliferation and immunofluorescence assays showed that rAj-Tspin suppressed the proliferation of Lewis lung carcinoma (LLC) cells through apoptosis. Adhesion assay also displayed that rAj-Tspin inhibited the adhesion of LLC cells to ECM proteins, including fibronectin, laminin, vitronectin and collagen. Lastly, rAj-Tspin also suppressed the migration and invasion of LLC cells across the filter in transwells. Thus, the above indicates that rAj-Tspin might act as a potential anti-tumoral drug in the future and could also provide information on the nutritional value of sea cucumber.
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Mori, Shiori, Rina Fujiwara-Tani, Shingo Kishi, Takamitsu Sasaki, Hitoshi Ohmori, Kei Goto, Chie Nakashima, et al. "Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer." International Journal of Molecular Sciences 22, no. 15 (July 30, 2021): 8232. http://dx.doi.org/10.3390/ijms22158232.
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β-Casomorphin-7 (BCM) is a degradation product of β-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes using an in vitro system comprising mouse splenocytes, a mouse colorectal carcinogenesis model, and a mouse orthotopic colorectal cancer model. Treatment of mouse splenocytes with BCM in vitro reduced numbers of cluster of differentiation (CD) 20+ B cells, CD4+ T cells, and regulatory T cells (Tregs), and increased CD8+ T cells. Administration of BCM and the CD10 inhibitor thiorphan (TOP) to mice resulted in similar alterations in the lymphocyte subsets in the spleen and intestinal mucosa. BCM was degraded in a concentration- and time-dependent manner by the neutral endopeptidase CD10, and the formed BCM degradation product did not affect the lymphocyte counts. Furthermore, degradation was completely suppressed by TOP. In the azoxymethane mouse colorectal carcinogenesis model, the incidence of aberrant crypt foci, adenoma, and adenocarcinoma was reduced by co-treatment with BCM and TOP. Furthermore, when CT26 mouse colon cancer cells were inoculated into the cecum of syngeneic BALB/c mice and concurrently treated with BCM and TOP, infiltration of CD8+ T cells was promoted, and tumor growth and liver metastasis were suppressed. These results suggest that by suppressing the BCM degradation system, the anti-tumor effect of BCM is enhanced and it can suppress the development and progression of colorectal cancer.
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Kim, Hyun-Jin, Jang Hyun Park, Hyeon Cheol Kim, Chae Won Kim, In Kang, and Heung Kyu Lee. "Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 84.11. http://dx.doi.org/10.4049/jimmunol.210.supp.84.11.
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Abstract Infiltrating tumor-associated macrophages (TAM) are known to impede immunotherapy against glioblastoma (GBM), however, TAMs are heterogeneous, and there are no clear markers to distinguish immunosuppressive and potentially immune-activating populations. Here we identify a subset of CD169+ macrophages promoting an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we find that CD169+ macrophages in human and mouse gliomas produce pro-inflammatory chemokines, leading to the accumulation of T cells and NK cells. CD169 expression on macrophages facilitates phagocytosis of apoptotic glioma cells and hence tumor-specific T cell responses. Depletion of CD169+ macrophages leads to functionally impaired antitumor lymphocytes and poorer survival of glioma-bearing mice. We show that NK-cell-derived IFN-γ is critical for the accumulation of blood monocyte-derived CD169+ macrophages in gliomas. Our work thus identifies a well-distinguished TAM subset promoting antitumor immunity against GBM, and identifies key factors that might shift the balance from immunosuppressive to anti-tumor TAM. This work was supported by Samsung Science and Technology Foundation (SSTF-BA1902-05), Republic of Korea. This work was also supported by the National Research Foundation of Korea grant (NRF-2021M3A9H3015688).
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Beissert, S., S. Grabbe, M. Voskort, T. A. Luger, T. Schwarz, and R. D. Granstein. "Effects of senescence on induction and elicitation of protective anti-tumoral immunity by langerhans cells in mice." Journal of Dermatological Science 16 (March 1998): S90. http://dx.doi.org/10.1016/s0923-1811(98)83534-2.
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Charrier, Emily, Rémi Vernet, Frank Schwenter, Patricia Luy, Alena Donda, and Nicolas Mach. "A Functional GM-CSF Receptor on Dendritic Cells Is Required for Efficient Protective Anti-Tumor Immunity." Immuno 1, no. 3 (August 6, 2021): 240–52. http://dx.doi.org/10.3390/immuno1030016.
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Dendritic cells (DC) play a major role during the priming phase of anti-tumor immunization, as they are required for an efficient tumor-associated antigens presentation. At least one dendritic cell-based therapy has already been successfully approved by regulators for clinical application in prostate cancer patients. Moreover, DC development is dependent on the granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been successfully used as a potent inducer of anti-tumoral immunity. To better understand the relation between DC and GM-CSF in anti-tumor immunity, we studied the DC function in mice lacking the cytokine receptor common subunit beta (βc-/-) for GM-CSF, IL-3 and IL-5 and immunized with irradiated tumor cells. Such immunization induces a protective, specific tumor immunization in wild-type mice, while βc-/- mice failed to mount an immune response. Upon in vitro stimulation, DC from βc-/- mice (DCβc-/-) are unable to undergo a full maturation level. In vivo experiments show that they lack the ability to prevent tumor growth, in contrast to DCWT. Moreover, matured DCWT rescued immunization in βc-/- mice. DC maturation is dependent on a functional pathway involving GM-CSF signaling through a biologically functional receptor. These findings may contribute to new strategies for efficient anti-tumor immunotherapies.
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Kim, Seon-Hee, Chungyong Han, Byoung S. Kwon, and Beom K. Choi. "CD4 depletion potentiates anti-tumor immunity in adoptive immunotherapy by increasing IL-18Rαhi endogenous CD8+ T cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 170.7. http://dx.doi.org/10.4049/jimmunol.204.supp.170.7.
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Abstract Adoptive T cell therapy (ACT) requires lympho-depletion pre-conditioning to eliminate immune-suppressive elements to allow for the efficient engraftment of adoptively transferred tumor-reactive T cells. Because anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells to enhance anti-tumor immunity, combinations of anti-CD4 treatment and ACT have synergistic potential in cancer therapy. We designed a post-ACT conditioning regimen that involves weekly treatment with anti-CD4 (CD4post). Using murine melanoma, cyclophosphamide and tumor-reactive CD8+ T cell infusion were included to represent an ACT model. We evaluated anti-tumor effects and immunologic changes of T cells. CD4post in ACT markedly increased tumor suppression and survival. Remarkably, CD4post worked differently on ex vivo primed CD8+ T cells versus endogenous CD8+ T cells. CD4post substantially increased the proliferation of ex vivo primed CD8+ T cells, while increasing endogenous CD8+ T cell differentiation and effector function. Endogenous CD8+ T cells upregulated activation/exhaustion markers and exhibited a skewed TCR repertoire, implying that CD4post boosted tumor-reactivity. Accordingly, CD4post-experienced endogenous CD8+ T cells showed enhanced intra-tumoral infiltration and exhibited greater anti-tumor activity against melanoma in vitro. Importantly, enrichment of the IL-18Rαhi subset was critical for boosting anti-tumor responses, as IL-18Rα+ cell-depletion CD8+ T cells resulted in diminished anti-tumor activity. This study highlights the clinical relevance of CD4post to ACT and gives insights into the characteristics of the immunological components that drive the augmented cancer–immunity cycle in ACT.
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Bishani, Ali, and Elena L. Chernolovskaya. "Activation of Innate Immunity by Therapeutic Nucleic Acids." International Journal of Molecular Sciences 22, no. 24 (December 12, 2021): 13360. http://dx.doi.org/10.3390/ijms222413360.
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Nucleic acid-based therapeutics have gained increased attention during recent decades because of their wide range of application prospects. Immunostimulatory nucleic acids represent a promising class of potential drugs for the treatment of tumoral and viral diseases due to their low toxicity and stimulation of the body’s own innate immunity by acting on the natural mechanisms of its activation. The repertoire of nucleic acids that directly interact with the components of the immune system is expanding with the improvement of both analytical methods and methods for the synthesis of nucleic acids and their derivatives. Despite the obvious progress in this area, the problem of delivering therapeutic acids to target cells as well as the unresolved issue of achieving a specific therapeutic effect based on activating the mechanism of interferon and anti-inflammatory cytokine synthesis. Minimizing the undesirable effects of excessive secretion of inflammatory cytokines remains an unsolved task. This review examines recent data on the types of immunostimulatory nucleic acids, the receptors interacting with them, and the mechanisms of immunity activation under the action of these molecules. Finally, data on immunostimulatory nucleic acids in ongoing and completed clinical trials will be summarized.
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Zhang, Tao, Yu Wang, Qing Li, Liangyu Lin, Chunliang Xu, Yueqing Xue, Mingyuan Hu, Yufang Shi, and Ying Wang. "Mesenchymal stromal cells equipped by IFNα empower T cells with potent anti-tumor immunity." Oncogene 41, no. 13 (February 10, 2022): 1866–81. http://dx.doi.org/10.1038/s41388-022-02201-4.
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AbstractCancer treatments have been revolutionized by the emergence of immune checkpoint blockade therapies. However, only a minority of patients with various tumor types have benefited from such treatments. New strategies focusing on the immune contexture of the tumor tissue microenvironment hold great promises. Here, we created IFNα-overexpressing mesenchymal stromal cells (IFNα-MSCs). Upon direct injection into tumors, we found that these cells are powerful in eliminating several types of tumors. Interestingly, the intra-tumoral injection of IFNα-MSCs could also induce specific anti-tumor effects on distant tumors. These IFNα-MSCs promoted tumor cells to produce CXCL10, which in turn potentiates the infiltration of CD8+ T cells in the tumor site. Furthermore, IFNα-MSCs enhanced the expression of granzyme B (GZMB) in CD8+ T cells and invigorated their cytotoxicity in a Stat3-dependent manner. Genetic ablation of Stat3 in CD8+ T cells impaired the effect of IFNα-MSCs on GZMB expression. Importantly, the combination of IFNα-MSCs and PD-L1 blockade induced an even stronger anti-tumor immunity. Therefore, IFNα-MSCs represent a novel tumor immunotherapy strategy, especially when combined with PD-L1 blockade.
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Rafei, M., J. Abusarah, and R. Shammaa. "The next generation cancer vaccines: genetically engineered mesenchymal stromal cells exhibit robust anti-tumoral immunity surpassing dendritic cells." Cytotherapy 22, no. 5 (May 2020): S31. http://dx.doi.org/10.1016/j.jcyt.2020.03.015.
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Cho, Jeong Hyun, Hyo-Ji Lee, Hyun-Jeong Ko, Byung-Il Yoon, Jongseon Choe, Keun-Cheol Kim, Tae-Wook Hahn, et al. "The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma." Oncotarget 8, no. 15 (February 15, 2017): 24932–48. http://dx.doi.org/10.18632/oncotarget.15326.
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Pandey, Sanjay, Claudia G. Chavez, Indranil Basu, Andy Minn, and Chandan Guha. "Abstract 3444: Administration of anti-CD40 enhances local and systemic antitumor efficacy of radiotherapy in allograft tumor model of a check-point blockade resistant melanoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3444. http://dx.doi.org/10.1158/1538-7445.am2022-3444.
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Abstract Resistance to immune checkpoint therapy develops in a subset of patients after initial response. Therefore, we hypothesized that defective antigen presentation contributes to immune resistance, and a sequential therapy comprising of ablative radiation therapy (RT) and agonist αCD40 antibody can reprogram the tumor-infiltrating myeloid and dendritic cells for effective in-situ tumor antigen presentation and activation of T cells. Palpable B16-F10-Res499 tumors in C57BL/6 mice, resistant to the systemic effects of RT and αCTLA-4 blockade, were treated with 3 fractions of 20Gy (RT) followed by agonist αCD40 antibody (3x100μg). Tumor growth, survival, and anti-tumoral immune memory after rechallenge was monitored. Mice were sacrificed on Day 16 post-RT, and immune cells from irradiated tumors and draining lymph nodes (DLN) were analyzed using flow cytometry. There was complete tumor regression and enhanced anti-tumoral immune memory in RT+αCD40-treated animals. In a dual tumor model, combination therapy significantly delayed abscopal tumor growth by 64% on D30 (p<0.0001). When compared to unirradiated or tumors treated with RT alone, there was a significant increase in cell surface expression of co-stimulatory molecules (CD80, CD86, CD40 and 4-1BBL) and TNF-α, and iNOS in the CD103+ DCs and myeloid cells (p<0.05) indicating a reprogramming of antigen presentation and co-stimulatory function in MDSCs. There was an increase in CD8+ T cells with reduced CD4/CD8 ratio (p<0.01) in abscopal tumors and DLN in the RT+αCD40 group. Combination treatment enhanced the frequency of proliferating Ki67+ (p<0.001) and IFNγ+ (p<0.01) CD8 T cells and an increase in the Ki67+ high GRZ+ (granzyme secreting) population in the pool of early exhausted cells (PD1intEOMESlow). Interestingly CD8 depletion by anti-CD8 only partially reversed the effect of the combination group. Furthermore, αCD40 showed an increase in the CD11b+Ly6C population in the tumors. Also, Ly6C depletion completely reversed the effect of the IR+anti-CD40 treatment. Conclusion: Combination of ablative RT, followed by αCD40 therapy, overcame immune resistance in murine melanoma by enhancing systemic anti-tumoral immunity, abscopal effects, survival, and anti-tumoral immune memory. The immunomodulatory effects of αCD40 are dependent upon Ly6C+ cells and partially on CD8+ T cells. Citation Format: Sanjay Pandey, Claudia G. Chavez, Indranil Basu, Andy Minn, Chandan Guha. Administration of anti-CD40 enhances local and systemic antitumor efficacy of radiotherapy in allograft tumor model of a check-point blockade resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3444.
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Poccia, F., B. Cipriani, S. Vendetti, V. Colizzi, Y. Poquet, L. Battistini, M. López-Botet, J. J. Fournié, and M. L. Gougeon. "CD94/NKG2 inhibitory receptor complex modulates both anti-viral and anti-tumoral responses of polyclonal phosphoantigen-reactive V gamma 9V delta 2 T lymphocytes." Journal of Immunology 159, no. 12 (December 15, 1997): 6009–17. http://dx.doi.org/10.4049/jimmunol.159.12.6009.
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Abstract Viral, bacterial, protozoal, and cancer-associated Ags elicit strong responses in human gammadelta T lymphocytes. The majority of these cells in the peripheral blood express the Vgamma9Vdelta2-encoded TCR and recognize nonpeptidic phosphoantigens without an apparent MHC restriction. We have shown that Vgamma9Vdelta2 T cells express the inhibitory CD94/NKG2 receptor for HLA class I molecules. The anti-CD94 mAb inhibits 1) the Vgamma9Vdelta2 T cell proliferation in response mycobacterial phosphoantigens and 2) the HIV-induced Vgamma9Vdelta2 T cell expansion. Vgamma9Vdelta2 T cells stimulated with nonpeptidic mycobacterial antigens produce IFN-gamma and TNF-alpha. Signaling through the CD94/NKG2 receptor interferes with the synthesis of these cytokines. The CD94/HLA class I interaction is also involved in the cytotoxic activity of Vgamma9Vdelta2 T cells. The Vgamma9Vdelta2 T cell regulation through the CD94 receptor may be important for the potentially dual function in innate immunity, i.e., 1) NK-like and 2) TCR ligand-induced cytolytic activities.
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Liu, Haiyan. "Differential roles of tumoral and systemic IL-1α in the development of hepatocellular carcinoma." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 178.24. http://dx.doi.org/10.4049/jimmunol.200.supp.178.24.
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Abstract Interleukin-1α (IL-1α) is a pro-inflammatory cytokine that has been shown to be up-regulated in many tumors. However, the role of IL-1α during tumor development is still not clear. IL-1α could be released by necrotic tumor cells passively to the tumor microenvironment or by other cells actively during inflammation. In the current study, we investigated the role of secreted IL-1α released in the tumor microenvironment or systemically in the tumor development using murine hepatocellular carcinoma (HCC) models. We constructed murine HCC hepa1-6 cells stably expressing secreted IL-1α and overexpression of secreted IL-1α had no significant effect on tumor cell proliferation and apoptosis in vitro. Tumor cells expressing secreted IL-1α were orthotopically implanted in the liver. Tumoral IL-1α significantly promoted HCC tumor development. Further studies showed that tumoral IL-1α inhibited T and NK cell activation, and attenuated the cytotoxic T lymphocyte (CTL) cytotoxic activity against tumor cells. Moreover, MDSCs were increased by tumoral IL-1α, and depletion of MDSCs could diminish the effect of the released IL-1α on tumor growth. On the contrary, systemic administration of IL-1α significantly inhibited the tumor development in the same murine HCC models. Systemic administration of IL-1α promoted T cell activation and decreased MDSCs in the tumor microenvironment. Further in vitro experiments showed that recombinant IL-1α could promote T cell activation and enhance CTL cytotoxicity. In conclusion, our studies demonstrated the differential functions of tumoral and systemic IL-1α in HCC development. Thus, our finding provides new insights of IL-1α functions in anti-tumor immunity with implications for tumor immunotherapy.
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Dorrier, Cayce, Felagot Abebe, Olivia Pak, Emily De-Bodene, and Joshua Wang. "Abstract LB117: Virus-inspired Particles (ViPs) harnessing cytomegalovirus immune memory for local and systemic cancer immunotherapy." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB117. http://dx.doi.org/10.1158/1538-7445.am2024-lb117.
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Abstract VerImmune is pioneering a First-in-Class treatment known as “Anti-tumor Immune Redirection” (AIR). This approach repurposes a patient’s pre-existing anti-viral or childhood vaccine immunity towards tumor cells for targeted destruction. VerImmune’s lead product, VERI-101, leverages pre-existing CD8+ T-cell immune memory acquired from past human cytomegalovirus (HCMV) infections. VERI-101 consists of VerImmune’s proprietary platform technology known as ViPs (Virus-inspired Particles) that are conjugated on their surface with a CD8+ T cell viral peptide antigen. ViPs are based on a modified mouse papillomavirus capsid protein of which 60 copies self-assemble into a 20-30nm T=1 icosahedral structure. In the case of VERI-101, the ViP is conjugated with an HLA-A*0201 restricted peptide epitope (NLVPMVATV, [NLV]), derived from the CMV pp65 antigen with an upstream furin protease cleavage site. The mechanism of action of AIR-ViPs including VERI-101 has been previously presented and involves three steps. Briefly, (1) VERI-101 targets the surface of the tumor cells and (2) enables the presentation of the CMV viral epitopes on their surface MHC, together (3) stimulating a recall of the pre-existing CMV memory response to attack the cancer cells (Dorrier et al., 2023 AACR). Here, we sought to study the in vivo anti-tumor efficacy of AIR-ViPs via both intra-tumoral and systemic treatment routes in two murine tumor models with pre-existing murine CMV (MCMV) immunity: (1) MC38 subcutaneous tumors for local and (2) B16.F10 lung metastasis for systemic treatments. As human CMV is species-specific, instead of VERI-101, a surrogate product, VERI-003 which redirects MCMV immunity, was tested as a single agent or in combination with anti-PD-1 in these tumor models. Our intra-tumoral studies with VERI-003 alone showed a dose-dependent anti-tumor effect (from 5 to 100ug) compared to no treatment controls. Surprisingly, no dose dependence was observed across the same three dose levels when combined with anti-PD-1, although significantly better anti-tumor effects occurred leading to complete tumor clearances in 50% of mice. Statistically significant prolonged survival was observed in most treated groups compared to controls. Our systemic studies with VERI-003 were consistent with our intratumoral studies in showing statistically significant single agent anti-tumor efficacy against B16.F10 lung metastases compared to no treatment. Anti-tumor effects of anti-PD-1 and combination were also observed. Additional studies are on-going to assess dose dependence and analysis of PK/PD effects. Taken together, our initial in vivo results demonstrate the tumor antigen-agnostic therapeutic potential of AIR and our AIR-ViP technology as a novel class of immuno-therapeutic drugs that could be used either as a monotherapy or in combination with checkpoint inhibitors. Citation Format: Cayce Dorrier, Felagot Abebe, Olivia Pak, Emily De-Bodene, Joshua Wang. Virus-inspired Particles (ViPs) harnessing cytomegalovirus immune memory for local and systemic cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB117.
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Awasthi, Deepika, and Aditya Sarode. "Neutrophils at the Crossroads: Unraveling the Multifaceted Role in the Tumor Microenvironment." International Journal of Molecular Sciences 25, no. 5 (March 2, 2024): 2929. http://dx.doi.org/10.3390/ijms25052929.
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Over the past decade, research has prominently established neutrophils as key contributors to the intricate landscape of tumor immune biology. As polymorphonuclear granulocytes within the innate immune system, neutrophils play a pivotal and abundant role, constituting approximately ∼70% of all peripheral leukocytes in humans and ∼10–20% in mice. This substantial presence positions them as the frontline defense against potential threats. Equipped with a diverse array of mechanisms, including reactive oxygen species (ROS) generation, degranulation, phagocytosis, and the formation of neutrophil extracellular traps (NETs), neutrophils undeniably serve as indispensable components of the innate immune system. While these innate functions enable neutrophils to interact with adaptive immune cells such as T, B, and NK cells, influencing their functions, they also engage in dynamic interactions with rapidly dividing tumor cells. Consequently, neutrophils are emerging as crucial regulators in both pro- and anti-tumor immunity. This comprehensive review delves into recent research to illuminate the multifaceted roles of neutrophils. It explores their diverse functions within the tumor microenvironment, shedding light on their heterogeneity and their impact on tumor recruitment, progression, and modulation. Additionally, the review underscores their potential anti-tumoral capabilities. Finally, it provides valuable insights into clinical therapies targeting neutrophils, presenting a promising approach to leveraging innate immunity for enhanced cancer treatment.
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Cannon, Anthony Michael, and Mark H. Kaplan. "IL-9 responsive macrophages utilize Arginase 1 to enhance lung tumor growth." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 84.09. http://dx.doi.org/10.4049/jimmunol.210.supp.84.09.
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Abstract In cancer, the immunosuppressive function of myeloid cells that support tumor progression is controlled by secreted factors in the tumor microenvironment. In the tumor microenvironment, arginine and arginine-derived metabolites have been demonstrated to be crucial factors in tumor development. Within macrophages, arginine metabolism influences the polarization of macrophages and therefore, tumor growth by eliciting an anti-tumoral or pro-tumoral phenotype. Interleukin 9 (IL-9) is a pleiotropic cytokine that signals through the IL-9 receptor (IL-9R) and can function as a positive or negative regulator in tumor immunity. Recently, our lab has demonstrated that IL-9 signaling promotes tumor progression in the lung by expanding pulmonary interstitial macrophage populations and inducing Arginase 1 (ARG1), an enzyme associated with pro-tumoral macrophage function, activity. However, the mechanism by which IL-9R/ARG1+ interstitial macrophages promote tumor development remains unknown. Here, using a B16F10 model of metastatic lung cancer, we demonstrate that knockdown of ARG1 using macrophage targeting Arg1siRNA containing nanoparticles results in altered pulmonary T-cell and macrophage proportions. Moreover, attenuation of IL-9 signaling and ARG1 expression in macrophages impacts arginine and arginine-derived metabolite concentration in lung tissue and BAL fluid which correlates with decreases in CD4+ T Cell exhaustion marker expression and a concomitant reduction in PDL1 expression on pulmonary interstitial macrophages in tumor-bearing mice. Thus, our work suggests that the IL-9R/ARG1 axis in macrophages is sufficient to alter arginine in the tumor microenvironment and promote tumor growth.
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Lan, Keng-Hsueh, Ying-Chun Sheng, Keng-Li Lan, KyungMann Kim, Sung-Hsin Kuo, and Zachary Morris. "Abstract 1098: Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1098. http://dx.doi.org/10.1158/1538-7445.am2023-1098.
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Abstract Background: Immune checkpoint blockade (ICB) immunotherapy improves survival for many cancer patients, but those with immunologically ‘cold’ tumors do not derive benefit. Radiation therapy (RT) has been demonstrated to augment antitumor immunity in preclinical and clinical studies and may enhance response to ICB in immunologically cold tumors. We have developed DNA-based, cost-effective, and versatile ICB immunotherapies. Here, we test the use of these alone and in combination with RT as a novel treatment approach in syngeneic murine melanoma models. Materials and methods: We constructed ICB DNA vaccines targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), CTLA-4 Vax and PD-1 Vax, respectively. These were delivered to mice by intramuscular or intratumoral electroporation. The effects of combinations of ICB DNA vaccines and RT were monitored for generation of endogenous anti-CTLA-4 and anti-PD-1 antibodies, modification of tumor microenvironment (TME), and tumor response in mice bearing syngeneic B78 or B16 melanoma. Results: Intramuscular vaccination with CTLA-4 Vax and PD-1 Vax induced endogenous anti-CTLA-4 and anti-PD-1 antibodies, respectively, and the titers increased with additional vaccinations. Vaccination with CTLA-4 Vax and PD-1 Vax alone or in combination (Dual Vax) did not inhibit the murine B16 melanoma model; however, the combination of CTLA-4 Vax and RT (CTLA-4 Vax + RT) led to enhanced infiltration of the TME with effector T cells. Dual Vax combined with RT enabled systemic anti-tumor immunity in mice bearing two B16 melanoma tumors in which only one was radiated. With intra-tumoral route of vaccination, the Dual Vax + RT treatment induced a trend toward systemic anti-tumor response in the immunologically cold B78 tumor model. Conclusions: DNA vaccines that stimulate endogenous production of antibodies against immune checkpoints may serve as an alternative form of ICB. The combination of ICB DNA vaccine and RT enabled anti-tumor immunity and tumor response in preclinical models of melanoma. Citation Format: Keng-Hsueh Lan, Ying-Chun Sheng, Keng-Li Lan, KyungMann Kim, Sung-Hsin Kuo, Zachary Morris. Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1098.
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Hoelzinger, Dominique, Ana Dominguez, Kevin Pollock, Joseph Lustgarten, Peter Cohen, and Sandra Gendler. "IL-9 strategy to perturb Treg function and enhance anti-tumor immunity (P4273)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 140.9. http://dx.doi.org/10.4049/jimmunol.190.supp.140.9.
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Abstract IL-9 is a cytokine that is primarily associated with mast cells and airway inflammation, however it also plays a role in T regulatory cell (Treg) survival and recruitment to tumors. We previously reported that 4-1BB treatment of Tregs inhibits both Treg function and IL-9 secretion. Neutralization of IL-9 with an anti-IL-9 antibody inhibits the suppressive function of Tregs without affecting the function of CD4+ and CD8+ T effector cells. Furthermore, the combination of intra-tumoral CpG and anti-IL-9 induced tumor rejection in BALB-neuT and MUC1 tolerant transgenic mice. Here we show that the lack of IL-9 inhibits Treg suppression of T cell proliferation, using IL-9 knockout (IL-9ko) mice. Phenotypic analysis of Treg markers showed that tumor draining lymph nodes of 4T1 bearing mice contain fewer CTLA-4+ and CD103+ Tregs, and that these also have reduced of CTLA-4 and CD103 expression. We also observed that IL-9ko mice spontaneously reject TUBO and 4T1 mammary carcinoma cells and that rejection is abrogated by CD8+ T cell depletion. Finally, preliminary studies of human CD4+ T cell proliferation revealed that IL-9 neutralization led to greater proliferation than isotype control treated cells. Taken together our results suggest that IL-9 can have an immunosuppressive function that comes into play in the tumor microenvironment, and that the blockade of IL-9 could serve as a novel strategy to perturb the function of Tregs to enhance the antitumor effect of tumor vaccines.
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Niavarani, Seyedeh Raheleh, Christine Lawson, and Lee-Hwa Tai. "Treatment of Metastatic Disease through Natural Killer Cell Modulation by Infected Cell Vaccines." Viruses 11, no. 5 (May 11, 2019): 434. http://dx.doi.org/10.3390/v11050434.
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Oncolytic viruses (OVs) are a form of immunotherapy that release tumor antigens in the context of highly immunogenic viral signals following tumor-targeted infection and destruction. Emerging preclinical and clinical evidence suggests that this in situ vaccine effect is critical for successful viro-immunotherapy. In this review, we discuss the application of OV as an infected cell vaccine (ICV) as one method of enhancing the potency and breadth of anti-tumoral immunity. We focus on understanding and manipulating the critical role of natural killer (NK) cells and their interactions with other immune cells to promote a clinical outcome. With a synergistic tumor killing and immune activating mechanism, ICVs represent a valuable new addition to the cancer fighting toolbox with the potential to treat malignant disease.
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Carrel, Sabrina, Michelle Li, Batul Al-Zubeidy, Dominic Zavala, Edgar Gonzales, Aaron Baugh, Sofi Castanon, et al. "Abstract A028: Disparities in suppressive immunity in Hispanic/Latina patients with hormone receptor positive breast cancer." Cancer Research 84, no. 3_Supplement_1 (February 1, 2024): A028. http://dx.doi.org/10.1158/1538-7445.advbc23-a028.
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Abstract In the US, breast cancer is the number one cancer diagnosed, and it is responsible for the most cancer related deaths among Hispanic/Latina (H/L) women. The mean age of diagnosis of breast cancer in H/L patients is 3.7 years younger than their Non-Hispanic White (NHW) counterparts. Despite being diagnosed with breast cancer at a younger age, the H/L population has a better overall survival rate across all breast cancer subtypes. This study investigates whether the immune response mounted against tumor cells in the H/L population differs from that mounted by NHW patients. We recruited and received consent from patients diagnosed with stage I- III (early stage), or stage IV/advanced (metastatic), hormone receptor positive (HR+) breast cancer. We collected blood from 66 patients (38 H/L, 28 NHW) across all stages of disease, and tumor tissue from 14 unmatched patients (7 H/L, 7 NHW), with early stage disease, at the time of tumor resection, none of whom had received neoadjuvant chemotherapy. We utilized multiparameter flow cytometry to analyze peripheral blood mononuclear cells (PBMCs), and 10X Visium for spatial transcriptomic and proteomic evaluation of patient’s tumor tissue to characterize differences in immune composition by race. We hypothesize that evaluation of intra-tumoral immune composition will reveal fewer immune suppressor cells and increased infiltration of cytotoxic immune cells in tumors from H/L patients. We also hypothesize evaluation of immune cells in circulation will mirror findings from within tumors. Suppressor immune cells, comprised of M2-polarized macrophages, myeloid derived suppressor cells (MDSCs), and T regulatory cells (Tregs) modulate T cell proliferation and cytotoxicity to affect anti-tumor immunity. We report a significant difference in the levels of both anti-tumoral and suppressive immune cells in the periphery within the H/L patient population when comparing early vs. metastatic HR+ breast cancer. This was not observed in the NHW group and there were no differences when comparing peripheral suppressor and T cell populations in H/L vs. NHW at any stage. Comparisons of intra-tumoral immune cell infiltration and differences in transcription profiles are forthcoming. The findings from this study will be some of the first to look at the immune composition in H/L women with HR+ disease, and could provide data to support larger studies leading to a paradigm shift in how we approach clinical trial design for immune checkpoint inhibition. Citation Format: Sabrina Carrel, Michelle Li, Batul Al-Zubeidy, Dominic Zavala, Edgar Gonzales, Aaron Baugh, Sofi Castanon, Robert Hsu, Dimitrios N Sidiropoulos, Yanling Ma, Michael Press, Evanthia T Roussos Torres. Disparities in suppressive immunity in Hispanic/Latina patients with hormone receptor positive breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A028.
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Everts, Anne, Melissa Bergeman, Grant McFadden, and Vera Kemp. "Simultaneous Tumor and Stroma Targeting by Oncolytic Viruses." Biomedicines 8, no. 11 (November 5, 2020): 474. http://dx.doi.org/10.3390/biomedicines8110474.
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Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their continuous complex interactions with tumor cells promote tumor progression and metastasis, emphasizing the challenges in tumor therapy development. Over the last decade, advances in oncolytic virotherapy have shown that oncolytic viruses (OVs) are a promising multi-faceted therapeutic platform for simultaneous tumor and stroma targeting. In addition to promoting tumor cell oncolysis and systemic anti-tumor immunity, accumulating data suggest that OVs can also directly target stromal components, facilitating OV replication and spread, as well as promoting anti-tumor activity. This review provides a comprehensive overview of the interactions between native and genetically modified OVs and the different targetable tumor stromal components, and outlines strategies to improve stroma targeting by OVs.
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Tiemeijer, Bart M., Lucie Descamps, Jesse Hulleman, Jelle J. F. Sleeboom, and Jurjen Tel. "A Microfluidic Approach for Probing Heterogeneity in Cytotoxic T-Cells by Cell Pairing in Hydrogel Droplets." Micromachines 13, no. 11 (November 4, 2022): 1910. http://dx.doi.org/10.3390/mi13111910.
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Cytotoxic T-cells (CTLs) exhibit strong effector functions to leverage antigen-specific anti-tumoral and anti-viral immunity. When naïve CTLs are activated by antigen-presenting cells (APCs) they display various levels of functional heterogeneity. To investigate this, we developed a single-cell droplet microfluidics platform that allows for deciphering single CTL activation profiles by multi-parameter analysis. We identified and correlated functional heterogeneity based on secretion profiles of IFNγ, TNFα, IL-2, and CD69 and CD25 surface marker expression levels. Furthermore, we strengthened our approach by incorporating low-melting agarose to encapsulate pairs of single CTLs and artificial APCs in hydrogel droplets, thereby preserving spatial information over cell pairs. This approach provides a robust tool for high-throughput and single-cell analysis of CTLs compatible with flow cytometry for subsequent analysis and sorting. The ability to score CTL quality, combined with various potential downstream analyses, could pave the way for the selection of potent CTLs for cell-based therapeutic strategies.
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Peggs, Karl S., Sergio A. Quezada, Tyler R. Simpson, and James P. Allison. "Dissociation of Systemic and Local Anti-Tumor Immunity Following Depletion of Regulatory T Cells Limits Therapeutic Activity in Established Tumors." Blood 110, no. 11 (November 16, 2007): 286. http://dx.doi.org/10.1182/blood.v110.11.286.286.
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Abstract Interference with the inhibitory immunological checkpoints controlling T-cell activation provides new opportunities to augment cancer immunotherapies. CD4+CD25+Foxp3+ T cells (Treg) are important regulators of T cell activity being largely responsible for the maintenance of peripheral self-tolerance. Evidence for their role in fostering immune privilege within tumors has fueled attempts to manipulate their number or function for therapeutic benefit. In pre-clinical tumor models, CD25-directed Treg depletion efficiently synergizes with various immune-based approaches but only when depletion occurs prior or close to the time of tumor challenge. Accordingly, depletion in clinical studies has failed to consistently enhance immunostimulatory strategies. CTLA-4 is a cell-intrinsic inhibitor of T cell activity, and blocking antibodies enhance anti-tumor activity in both pre-clinical and clinical studies. Using in vivo murine models we combined a GM-CSF-secreting cellular vaccine (Gvax), CTLA-4-blockade and CD25-directed Treg depletion (using αCD25 monoclonal antibody either before [prophylactic] or after [therapeutic] tumor challenge) and studied their effects on systemic and local anti-tumor immunity. In contrast to prophylactic Treg depletion, therapeutic depletion failed to promote tumor rejection; this correlated with a lack of accumulation of T-cells within the tumor. Gvax/αCTLA-4 induced systemic accumulation of Treg which was prevented by Treg depletion regardless of its timing. Systemic anti-tumor responses were comparable as shown by similar T cell proliferation profiles and similar numbers of tumor-specific IFN-producing cells, suggesting that failure of therapeutic depletion to enhance rejection was unrelated to depletion of CD25+ effector T cells (Teff). Foxp3-directed depletion (in Foxp3-DTR mice) confirmed these findings. Similar effects in adoptively transferred antigen-specific transgenic CD8+ T cells verify the relevance of these data to tumor-specific T cells. Within the tumor, αCD25 drove mainly CD8+ T cells into cell cycle, compared to mainly CD4+Foxp3− T cells with Gvax/αCTLA-4. Combination had an additive effect, inducing the proliferation of the whole Teff compartment regardless of the timing of αCD25. Intra-tumoral Foxp3+ Treg were in cycle independent of therapy, suggesting a constant turnover. Given the similarities in systemic immunity and proliferative responses of the infiltrating populations regardless of αCD25 timing, but marked differences in the numbers of cells accumulating within the tumor, we focused on the possibility that differences in migration from the vascular compartment might explain our observations. Only prophylactic αCD25 led to expression of endothelial activation markers on tumor vasculature, which directly correlated with intra-tumoral T cell accumulation and tumor rejection. Importantly, systemic anti-tumor activity was transferable from mice receiving therapeutic depletion into tumor-bearing recipients after non-myeloablative conditioning, resulting in activation of the vascular endothelium, T cell infiltration and tumor rejection. Our data demonstrate the potential of vaccination strategies to induce counter-productive immuno-inhibitory host responses and reveal a dichotomy between systemic and local anti-tumor immunity following therapeutic Treg depletion. Finally, they support an alternative strategy for the treatment of established tumors in humans that exploits the augmented systemic immunity induced by vaccination following Treg depletion.
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Saito, Yasuyuki, Satomi Komori, Takenori Kotani, Yoji Murata, and Takashi Matozaki. "The Role of Type-2 Conventional Dendritic Cells in the Regulation of Tumor Immunity." Cancers 14, no. 8 (April 13, 2022): 1976. http://dx.doi.org/10.3390/cancers14081976.
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Conventional dendritic cells (cDCs) orchestrate immune responses to cancer and comprise two major subsets: type-1 cDCs (cDC1s) and type-2 cDCs (cDC2s). Compared with cDC1s, which are dedicated to the activation of CD8+ T cells, cDC2s are ontogenically and functionally heterogeneous, with their main function being the presentation of exogenous antigens to CD4+ T cells for the initiation of T helper cell differentiation. cDC1s play an important role in tumor-specific immune responses through cross-presentation of tumor-derived antigens for the priming of CD8+ T cells, whereas little is known of the role of cDC2s in tumor immunity. Recent studies have indicated that human cDC2s can be divided into at least two subsets and have implicated these cells in both anti- and pro-tumoral immune responses. Furthermore, the efficacy of cDC2-based vaccines as well as cDC2-targeted therapeutics has been demonstrated in both mouse models and human patients. Here we summarize current knowledge about the role of cDC2s in tumor immunity and address whether these cells are beneficial in the context of antitumor immune responses.
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Orlandella, Rachael M., Shannon Boi, Daniel Smith, and Lyse A. Norian. "Understanding the effects of a calorie restriction mimetic on renal cancer progression and CD8 T cell immunity." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 76.12. http://dx.doi.org/10.4049/jimmunol.198.supp.76.12.
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Abstract Metastatic renal cell carcinoma (RCC) exhibits high mortality rates and chemotherapeutic resistance. Immune-based therapies, including high-dose IL-2 and anti-PD1, are efficacious in ~20% of patients; however, both are associated with substantial toxicity. This highlights the need for additional research aimed at improving response rates while also limiting toxicity. Previous findings by other groups have demonstrated that nutrient deprivation prior to chemotherapy reduces treatment toxicity and may improve therapeutic efficacy in cancer patients. Recent murine research shows that diets containing calorie restriction mimetics (CRMs) can recapitulate these beneficial effects by enhancing anti-cancer immunity. Here, we examined the impact of the alpha-glucosidase inhibitor acarbose, a potential CRM, on renal tumor burden and immune profiles. BALB/c mice were fed an acarbose-containing diet or macronutrient-matched control diet for 4 weeks prior to challenge with syngeneic Renca renal carcinoma cells. Although no significant differences were observed in primary renal tumor outgrowth or spontaneous lung metastases (both, p<0.05), acarbose-fed mice exhibited severe weight loss following intra-renal tumor challenge (p=0.02). Tumor-bearing mice fed an acarbose diet displayed increased percentages of total splenic (p=0.03) and intra-tumoral (p=0.04) CD8 T cells versus controls. Future experiments will evaluate the effects of the acarbose CRM on immunotherapeutic efficacy and ensuing immune responses. Our findings demonstrate that further research is required to understand how specific CRMs impact tumor outgrowth and anti-cancer immunity.
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Crescenzi, Elvira, Antonio Leonardi, and Francesco Pacifico. "NGAL as a Potential Target in Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 22 (November 15, 2021): 12333. http://dx.doi.org/10.3390/ijms222212333.
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The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy.
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Guth, Amanda, Emily Monk, Rajesh Agarwal, Bryan C. Bergman, Karin A. Zemski-Berry, Angela Minic, Kimberly Jordan, and Isabel R. Schlaepfer. "Targeting Fat Oxidation in Mouse Prostate Cancer Decreases Tumor Growth and Stimulates Anti-Cancer Immunity." International Journal of Molecular Sciences 21, no. 24 (December 18, 2020): 9660. http://dx.doi.org/10.3390/ijms21249660.
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Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined the pharmacological blockade of lipid oxidation with ranolazine in TRAMPC1 PCa models. Oral administration of ranolazine (100 mg/Kg for 21 days) resulted in decreased tumor CD8+ T-cells Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes. Using multispectral staining, drug treatments increased infiltration of CD8+ T-cells and dendritic cells compared to vehicle. Functional studies with spleen cells of drug-treated tumors co-cultured with TRAMPC1 cells showed increased ex vivo T-cell cytotoxic activity, suggesting an anti-tumoral response. Lastly, a decrease in CD4+ and CD8+ T-cells expressing PD1 was observed when exhausted spleen cells were incubated with TRAMPC1 Cpt1a-KD compared to the control cells. These data indicated that genetically blocking the ability of the tumor cells to oxidize lipid can change the activation status of the neighboring T-cells. This study provides new knowledge of the role of lipid catabolism in the intercommunication of tumor and immune cells, which can be extrapolated to other cancers with high CPT1A expression.
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Cano, Carla E., Christine Pasero, Aude De Gassart, René Hoet, Emmanuel Scotet, Erwan Mortier, Agnes Quemeneur, et al. "BTN2A, a New Immune-Checkpoint Targeting Vg9Vd2 T Cell Cytotoxicity." Blood 134, Supplement_1 (November 13, 2019): 1044. http://dx.doi.org/10.1182/blood-2019-128658.
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Background: Anti-tumoral response of Vg9Vd2 T cells requires sensing of phosphoantigens accumulated in malignant cells through binding of butyrophilin 3A(BTN3A). Moreover, an unknown partner located in human Chr6 was shown to be mandatory to BTN3A-mediated Vg9Vd2 T cell activation in murine models. Here, we identified butyrophilin 2A (BTN2A), which is located to Chr6, as a requirement for BTN3A-mediated Vg9Vd2 T cell cytotoxicity against cancer cells. Methods: CRISPR-Cas9-mediated inactivation of BTN2A1/2A2 isoforms was performed in Daudi, K562 and HEK-293T cells. Vg9Vd2 T cells expanded from healthy PBMCs were co-cultured with wild-type or BTN2AKO cells +/- BrHPP (1 µM), HMBPP (0.1 µM) or zoledronate (45 µM), or anti-BTN2A mAb, and Vg9Vd2 T cell degranulation (%CD106ab+ cells), and intracellular TNFa and IFNg assessed after 4h. Mouse T cell hybridoma 53/4 expressing TCRVg9Vd2-MOP were co-cultured overnight with NIH3T3 murine fibroblasts transfected with BTN3A- and/or BTN2A-encoding plasmids +/-HMBPP(10 µM), or increasing doses of HMBPP or anti-BTN3 20.1 mAb. BTN2A transcript expression in normal vs. tumoral tissue was analyzed using GEPIA tool. Anti-BTN2A mAb staining was performed on human samples of primary AML, cervical and pancreatic carcinoma and assessed by flow cytometry. Results: Degranulation and intracellular IFNg/TNFa (n=6) were abolished in Vg9Vd2 T cells co-cultured with BTN2AKO Daudi, K562 and HEK-293T cells compared to wild-type, in all conditions tested including anti-BTN3 20.1. Murine cells do not express no BTN2A1 or BTN3A orthologs and are unable to activate human Vg9Vd2 T cells. Ectopic expression of BTN2A and BTN3A combination but neither BTN2A or BTN3A alone in murine NIH3T3 cells, allows triggering of IL-2 secretion in mouse 53/4-TCRVg9Vd2-MOP reporter cells in presence of HMBPP or 20.1 mAb in dose-dependent manner. Anti-BTN2A mAb was able to suppress Vg9Vd2 T cell degranulation/cytokine secretion against cancer cell lines and activation of mouse 53/4-TCRVg9Vd2-MOP reporter by BTN2A/BTN3A-expressing NIH3T3 in a dose-dependent manner. BTN2A transcript was significantly up-regulated in pancreatic, ovarian and cervical carcinoma vs. normal tissue. Extracellular BTN2A protein was detected in primary hematological and solid tumors. Conclusion: Here, we show that BTN2A is mandatory for BTN3A-mediated function in human Vg9Vd2 T cells. Moreover, concomitant BTN2A and BTN3A expression empowers murine T cells with activation through Vg9Vd2 TCR, opening new roads for mouse models of Vg9Vd2 T cell anti-tumoral responses. We describe an anti-BTN2A able to suppress Vg9Vd2 T cell function, and we show BTN2A expression in primary tumors. These results are relevant for understanding Vg9Vd2 T cell antitumoral immunity triggered by phosphoantigens and amino-bisphosphonates. Disclosures Olive: ImCheck Therapeutics: Consultancy, Equity Ownership, Patents & Royalties; GlaxoSmithKline: Patents & Royalties.
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Bruno, Gennaro, Nicoletta Nastasi, Angela Subbiani, Alessia Boaretto, Annalisa Tondo, Claudio Favre, and Maura Calvani. "Abstract 3887: β3-adrenergic receptor sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in neuroblastoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3887. http://dx.doi.org/10.1158/1538-7445.am2022-3887.
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Abstract In this study we aimed to investigate the role of the β3-adrenergic receptor (β3-AR) in regulating the immune system response against neuroblastoma (NB) tumor. NB is a very heterogeneous extracranial tumor occurring in childhood. A distinctive feature of NB tumors is their neuroendocrine ability to secrete catecholamines, which in turn, via β-adrenergic receptors ligation, may affect different signaling pathways in the tumor microenvironment (TME). We previously demonstrated that the specific antagonism of the β3-AR on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB (A/J mice inoculated with the murine neuroblastoma cell line Neuro-2a), the β3-AR blockade ability to influence the number of immunoreactive and/or immunosuppressive cells in TME was investigated through flow cytometry analysis. Moreover, the involvement of the immune-checkpoint signaling axis PD-1/PD-L1 in mediating the anti-tumoral effects brought by a β3-AR antagonist administration was analyzed. Results demonstrated that β3-AR antagonism leads to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, β3-AR antagonism was able to increase the number of immune reactive CD8+, natural killer (NK) and dendritic cells (DCs), and to decrease the number of immune suppressive regulatory T cells (Treg) and Myeloid-derived suppressor cells (MDSC) in tumor mass. Moreover, β3-AR blockade on tumor infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ, which in turn reduced the PD-L1 expression on NB tumor cells. Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates negatively with the patient’s clinical outcome compared to the low expression group, and that ADRB3 gene expression is also related to the expression of different immune-checkpoints. Overall, results indicate that β3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways. Citation Format: Gennaro Bruno, Nicoletta Nastasi, Angela Subbiani, Alessia Boaretto, Annalisa Tondo, Claudio Favre, Maura Calvani. β3-adrenergic receptor sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3887.