Journal Articles

Cancer Immunobiology

Basic research studies that extend knowledge in the field of cancer immunotherapy

Natural killer cells and other innate lymphoid cells in cancer

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Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.

Author Info: (1) Innate Pharma Research Labs, Innate Pharma, Marseille, France. Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (2) Aix Marseille University, CNRS, INSERM, CIML, Marseille

Author Info: (1) Innate Pharma Research Labs, Innate Pharma, Marseille, France. Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (2) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. CHU Bordeaux, Service d'Hematologie Clinique et Therapie Cellulaire, F-33000, Bordeaux, France. (3) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (4) Innate Pharma Research Labs, Innate Pharma, Marseille, France. vivier@ciml.univ-mrs.fr. Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. vivier@ciml.univ-mrs.fr. Service d'Immunologie, Marseille Immunopole, Hopital de la Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France. vivier@ciml.univ-mrs.fr.

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Chemotherapy Combines Effectively with Anti-PD-L1 Treatment and Can Augment Antitumor Responses

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Immunotherapy with checkpoint inhibitors has proved to be highly effective, with durable responses in a subset of patients. Given their encouraging clinical activity, checkpoint inhibitors are increasingly being tested in clinical trials in combination with chemotherapy. In many instances, there is little understanding of how chemotherapy might influence the quality of the immune response generated by checkpoint inhibitors. In this study, we evaluated the impact of chemotherapy alone or in combination with anti-PD-L1 in a responsive syngeneic tumor model. Although multiple classes of chemotherapy treatment reduced immune cell numbers and activity in peripheral tissues, chemotherapy did not antagonize but in many cases augmented the antitumor activity mediated by anti-PD-L1. This dichotomy between the detrimental effects in peripheral tissues and enhanced antitumor activity was largely explained by the reduced dependence on incoming cells for antitumor efficacy in already established tumors. The effects of the various chemotherapies were also agent specific, and synergy with anti-PD-L1 was achieved by different mechanisms that ultimately helped establish a new threshold for response. These results rationalize the combination of chemotherapy with immunotherapy and suggest that, despite the negative systemic effects of chemotherapy, effective combinations can be obtained through distinct mechanisms acting within the tumor.

Author Info: (1) Genentech, South San Francisco, CA 94080; and cubasr@gene.com. (2) Genentech, South San Francisco, CA 94080; and. (3) Genentech, South San Francisco, CA 94080; and

Author Info: (1) Genentech, South San Francisco, CA 94080; and cubasr@gene.com. (2) Genentech, South San Francisco, CA 94080; and. (3) Genentech, South San Francisco, CA 94080; and. (4) Genentech, South San Francisco, CA 94080; and. (5) Genentech, South San Francisco, CA 94080; and. (6) Genentech, South San Francisco, CA 94080; and. (7) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (8) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (9) Genentech, South San Francisco, CA 94080; and. (10) Genentech, South San Francisco, CA 94080; and.

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Murine Pre-B cell ALL induces T cell dysfunction not fully reversed by introduction of a chimeric antigen receptor

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Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CART) has demonstrated dramatic success in relapsed/refractory pre-B cell ALL but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T cell function but this has not been well studied in ALL and in the context of CAR expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors including PD1, Tim3 and LAG3 and were dysfunctional following adoptive transfer in a model of TCR-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B ALL induced inhibitory receptor expression, at least in part, via a T cell receptor (TCR) independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

Author Info: (1) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (2) Hematologic Malignancies

Author Info: (1) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (2) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (3) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (4) Howard Hughes Medical Institute, Chevy Chase, MD, United States. (5) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (6) CCBR Bioinformatics, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, United States. (7) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (8) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (9) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (10) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (11) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; terry.fry@ucdenver.edu.

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Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF-beta Inhibitor Sequencing in Melanoma

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Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacological inhibition of the TGF-beta signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAF(V600E) melanoma. Additional mechanistic studies revealed that TGF-beta pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby, facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGF-beta signaling activity. Delayed TGF-beta inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGF-beta inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGF-beta inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance.

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, Duke University Medical Center

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, Duke University Medical Center. (5) Internal Medicine/Medical Oncology, Duke University Medical Center. (6) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (7) Internal Medicine III, University Hospital Regensburg. (8) Pharmacology & Cancer Biology, Duke University Medical Center. (9) Internal Medicine/Medical Oncology and Pharmacology/Cancer Biology, Duke University Medical Center hanks004@mc.duke.edu.

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Immunomodulation Mediated by Anti-angiogenic Therapy Improves CD8 T Cell Immunity Against Experimental Glioma

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Glioblastoma (GBM) is a lethal cancer of the central nervous system with a median survival rate of 15 months with treatment. Thus, there is a critical need to develop novel therapies for GBM. Immunotherapy is emerging as a promising therapeutic strategy. However, current therapies for GBM, in particular anti-angiogenic therapies that block vascular endothelial growth factor (VEGF), may have undefined consequences on the efficacy of immunotherapy. While this treatment is primarily prescribed to reduce tumor vascularization, multiple immune cell types also express VEGF receptors, including the most potent antigen-presenting cell, the dendritic cell (DC). Therefore, we assessed the role of anti-VEGF therapy in modifying DC function. We found that VEGF blockade results in a more mature DC phenotype in the brain, as demonstrated by an increase in the expression of the co-stimulatory molecules B7-1, B7-2, and MHC II. Furthermore, we observed reduced levels of the exhaustion markers PD-1 and Tim-3 on brain-infiltrating CD8 T cells, indicating improved functionality. Thus, anti-angiogenic therapy has the potential to be used in conjunction with and enhance immunotherapy for GBM.

Author Info: (1) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States. (2) Department

Author Info: (1) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States. (2) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States. (3) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (4) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (5) Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States. (6) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (7) Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States. (8) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (9) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Department of Neurology, Mayo Clinic, Rochester, MN, United States. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States.

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Type II NKT Cells: An Elusive Population With Immunoregulatory Properties

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Natural killer T (NKT) cells are unique unconventional T cells that are reactive to lipid antigens presented on the non-polymorphic major histocompatibility class (MHC) I-like molecule CD1d. They have characteristics of both innate and adaptive immune cells, and have potent immunoregulatory roles in tumor immunity, autoimmunity, and infectious diseases. Based on their T cell receptor (TCR) expression, NKT cells are divided into two subsets, type I NKT cells with an invariant TCRalpha-chain (Valpha24 in humans, Valpha14 in mice) and type II NKT cells with diverse TCRs. While type I NKT cells are well-studied, knowledge about type II NKT cells is still limited, and it is to date only possible to identify subsets of this population. However, recent advances have shown that both type I and type II NKT cells play important roles in many inflammatory situations, and can sometimes regulate the functions of each other. Type II NKT cells can be both protective and pathogenic. Here, we review current knowledge on type II NKT cells and their functions in different disease settings and how these cells can influence immunological outcomes.

Author Info: (1) Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (2) Department of Microbiology and Immunology, Institute of Biomedicine

Author Info: (1) Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (2) Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (3) Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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Long-term survival of locally advanced stage III non-small cell lung cancer patients treated with chemoradiotherapy and perspectives for the treatment with immunotherapy

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Background Standard treatment for patients with inoperable locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT). Five-year overall survival rates range between 15 and 25%, while long term survival data are rarely reported. Patients and methods A total of 102 patients with stage III NSCLC treated between September 2005 and November 2010 with induction chemotherapy and CCRT were included in this long term survival analysis. All patients were tested for PD-L1 status and expression of PD-L1 was correlated with overall survival (OS), progression free survival (PFS) and toxicities. Results The median OS of all patients was 24.8 months (95% CI 18.7 to 31.0) with 10 year-survival rate of 11.2%. The median OS of patients with PD-L1 expression was 12.1 months (95% CI 0.1 to 26.2), while in patients with negative or unknown PD-L1 status was significantly longer, 25.2 months (95% CI 18.9 to 31.6), p = 0.005. The median PFS of all patients was 16.4 months (95% CI 13.0 to 19.9). PFS of patients with PD-L1 expression was 10.1 months (95% CI 0.1 to 20.4) and in patients with negative or unknown PD-L1 status was 17.9 months (95% CI 14.2 to 21.7), p = 0.003. Conclusions 10-year overall survival of stage III NSCLC patients after CCRT is 11.2%. PFS and OS differ with regard to PD-L1 status and are significantly shorter for patients with PD-L1 expression. New treatment with check-point inhibitors combined with RT therefore seems reasonable strategy to improve these results.

Author Info: (1) Institute of Oncology Ljubljana, Ljubljana, Slovenia. (2) Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Author Info: (1) Institute of Oncology Ljubljana, Ljubljana, Slovenia. (2) Institute of Oncology Ljubljana, Ljubljana, Slovenia.

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Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience

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BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG. METHODS: We performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT. RESULTS: Thirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity. CONCLUSIONS: Our experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy.

Author Info: (1) Department of Pediatrics, University of California, San Francisco, CA, USA. cassie.kline@ucsf.edu. Department of Neurology, University of California, San Francisco, CA, USA. cassie.kline@ucsf.edu. (2) School

Author Info: (1) Department of Pediatrics, University of California, San Francisco, CA, USA. cassie.kline@ucsf.edu. Department of Neurology, University of California, San Francisco, CA, USA. cassie.kline@ucsf.edu. (2) School of Medicine, University of California, San Francisco, CA, USA. (3) Department of Radiation Oncology, Washington University in Saint Louis, St Louis, MO, USA. (4) Department of Pediatrics, University of California, San Francisco, CA, USA. Department of Neurological Surgery, University of California, San Francisco, CA, USA. (5) Department of Neurological Surgery, University of California, San Francisco, CA, USA. Department of Pediatrics, New York University, New York, NY, USA. (6) Department of Pediatrics, University of California, San Francisco, CA, USA. (7) Department of Pediatrics, University of California, San Francisco, CA, USA. Department of Neurological Surgery, University of California, San Francisco, CA, USA. (8) Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA, USA. (9) Department of Radiation Oncology, University of California, San Francisco, CA, USA. (10) Department of Pediatrics, University of California, San Francisco, CA, USA. sabine.mueller@ucsf.edu. Department of Neurology, University of California, San Francisco, CA, USA. sabine.mueller@ucsf.edu. Department of Neurological Surgery, University of California, San Francisco, CA, USA. sabine.mueller@ucsf.edu.

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Antibody-Fc/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non-Small Cell Lung Cancer Subsequent to PD-1/PD-L1 Blockade

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PURPOSE: Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinico-pathological features nor biological mechanisms associated with HP have been identified. EXPERIMENTAL DESIGN: Among 187 patients with non-small cell lung cancer (NSCLC) treated with ICI at our Institute, cases with HP were identified according to clinical and radiological criteria. Baseline histological samples from patients treated with ICI were evaluated by immunohistochemistry (IHC) for myeloid and lymphoid markers. T-cell deficient mice, injected with human lung cancer cells and patient-derived xenografts (PDXs) belonging to specific mutational subsets, were assessed for tumor growth after treatment with antibodies against mouse and human programmed death receptor-1 (PD-1). The immune microenvironment was evaluated by flow cytometry and IHC. RESULTS: Among 187 patients, 152 were evaluable for clinical response. We identified 4 categories: 32 cases were defined as Responders (21%), 42 patients with Stable Disease (27.7%), 39 cases defined as Progressors (25.7%) and 39 patients with HP (25.7%). Pre-treatment tissue samples from all patients with HP showed tumor-infiltration by M2-like CD163+CD33+PD-L1+ clustered epithelioid macrophages. Enrichment by tumor-associated macrophages (TAM) was observed, even in tumor nodules from immunodeficient mice injected with human lung cancer cells and with PDXs. In these models, tumor growth was enhanced by treatment with anti-PD-1, but not by anti-PD-1 F(ab)2-fragments. CONCLUSIONS: These results suggest a crucial role of TAM reprogramming, upon Fc receptor engagement by ICI, eventually inducing HP and provide clues on a distinctive immunophenotype potentially able to predict HP.

Author Info: (1) Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori. (2) Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei

Author Info: (1) Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori. (2) Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori. (3) Dipartimento di Scienze Biomediche per la Salute, Universita degli Studi di Milano. (4) Tumor Immunology Unit, Department of Health Sciences, University of Palermo. (5) Unit of Tumor Genomics, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori. (6) Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori. (7) Department of Research, Fondazione IRCCS Istituto Nazionale Tumori. (8) Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori. (9) Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori. (10) Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori. (11) Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori. (12) Oncology, Mario Negri Institute for Pharmacological Research. (13) Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori. (14) Pathology and Laboratory Medicine, European Institute of Oncology. (15) Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori. (16) Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori. (17) Dipartimento di Scienze Biomediche per la Salute, University of Milan. (18) Dipartimento di Scienze Biomediche per la Salute, Universita degli Studi di Milano. (19) Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Hospital. (20) Molecular Oncology, Candiolo Cancer Institute - FPO, IRCCS. (21) Clinical Coordination Unit, Institute for Cancer Research and Treatment. (22) Department of Oncology, Mario Negri Institute. (23) Tumor Immunology Unit, Department of Health Science, University of Palermo School of Medicine. (24) Fondazione IRCCS Istituto Nazionale Tumori. (25) Dept. of Research, Fondazione IRCCS Istituto Nazionale dei Tumori. (26) Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori. (27) Dipartimento di Scienze Biomediche per la Salute, Universita degli Studi di Milano. (28) Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori gabriella.sozzi@istitutotumori.mi.it. (29) NCI Milan.

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The Role of IL-33/ST2 Pathway in Tumorigenesis

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Cancer is initiated by mutations in critical regulatory genes; however, its progression to malignancy is aided by non-neoplastic cells and molecules that create a permissive environment known as the tumor stroma or microenvironment (TME). Interleukin 33 (IL-33) is a dual function cytokine that also acts as a nuclear factor. IL-33 typically resides in the nucleus of the cells where it is expressed. However, upon tissue damage, necrosis, or injury, it is quickly released into extracellular space where it binds to its cognate receptor suppression of tumorigenicity 2 (ST2)L found on the membrane of target cells to potently activate a T Helper 2 (Th2) immune response, thus, it is classified as an alarmin. While its role in immunity and immune-related disorders has been extensively studied, its role in tumorigenesis is only beginning to be elucidated and has revealed opposing roles in tumor development. The IL-33/ST2 axis is emerging as a potent modulator of the TME. By recruiting a cohort of immune cells, it can remodel the TME to promote malignancy or impose tumor regression. Here, we review its multiple functions in various cancers to better understand its potential as a therapeutic target to block tumor progression or as adjuvant therapy to enhance the efficacy of anticancer immunotherapies.

Author Info: (1) Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA. kmlarsen@email.sc.edu. (2) Department of Biological Sciences, University of South Carolina, Columbia, SC

Author Info: (1) Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA. kmlarsen@email.sc.edu. (2) Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA. maydelis_minaya@brown.edu. (3) Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA. vivekvaish@live.com. (4) Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA. mpena@biol.sc.edu.

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