Journal Articles

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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B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma

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Knowledge of PD-L1 expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-PD-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may also identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in non-germinal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found in PD-L1-positive B-cell lymphoma cells that BCR-mediated NFATc1 activation up-regulates IL-10 chemokine expression. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks both NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in two primary DLBCL cohorts, consisting of 428 and 350 cases and showed significant correlations between IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.

Author Info: (1) Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China. (2) Department of Hematopathology, The University of Texas MD Anderson Cancer Center

Author Info: (1) Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China. (2) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (3) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (4) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (5) Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China. (6) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (7) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (8) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (9) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (10) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (11) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (12) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; lvpham@mdanderson.org.

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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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Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

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Immunotherapy is showing promise for otherwise incurable cancers. Oncolytic viruses (OVs), developed as direct cytotoxic agents, mediate their antitumor effects via activation of the immune system. However, OVs also stimulate antiviral immune responses, including the induction of OV-neutralizing antibodies. Current dogma suggests that the presence of preexisting antiviral neutralizing antibodies in patients, or their development during viral therapy, is a barrier to systemic OV delivery, rendering repeat systemic treatments ineffective. However, we have found that human monocytes loaded with preformed reovirus-antibody complexes, in which the reovirus is fully neutralized, deliver functional replicative reovirus to tumor cells, resulting in tumor cell infection and lysis. This delivery mechanism is mediated, at least in part, by antibody receptors (in particular FcgammaRIII) that mediate uptake and internalization of the reovirus/antibody complexes by the monocytes. This finding has implications for oncolytic virotherapy and for the design of clinical OV treatment strategies. Cancer Immunol Res; 1-13. (c)2018 AACR.

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (3) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (4) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (5) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (6) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (7) Oncolytics Biotech Incorporated, Calgary, Alberta, Canada. (8) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (9) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (10) Institute of Cancer Research, London, United Kingdom. (11) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. e.ilett@leeds.ac.uk.

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CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth

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The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-gamma in vitro. BCMA-dependent cytotoxicity and IFN-gamma secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.

Author Info: (1) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. robert.berahovich@promab.com. (2) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. huazhou369@gmail.com. (3) ProMab Biotechnologies

Author Info: (1) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. robert.berahovich@promab.com. (2) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. huazhou369@gmail.com. (3) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. shirley.xu@promab.com. (4) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. yuehua.wei@promab.com. (5) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. jasper.guan@promab.com. (6) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. jian.guan@promab.com. (7) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. hizkia.harto@promab.com. (8) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. promab8807@126.com. (9) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. yangkaihuai520@126.com. (10) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. shuying256@163.com. (11) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. simon.li@promab.com. Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. simon.li@promab.com. (12) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. john@promab.com. (13) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. vita.gol@promab.com.

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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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TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

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Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naive immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

Author Info: (1) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (2) Department of Biosciences, Centre for

Author Info: (1) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (2) Department of Biosciences, Centre for Immune Regulation, University of Oslo, N-0316 Oslo, Norway. Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, Norway. (3) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (4) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (5) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (6) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (7) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (8) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (9) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (10) MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom. (11) Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. (12) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (13) MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom. (14) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (15) Department of Biosciences, Centre for Immune Regulation, University of Oslo, N-0316 Oslo, Norway. Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, Norway. (16) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; lcj@mrc-lmb.cam.ac.uk.

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Co-inhibition of TIGIT, PD1, and Tim3 reverses dysfunction of Wilms tumor protein-1 (WT1)-specific CD8+ T lymphocytes after dendritic cell vaccination in gastric cancer

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Dendritic cell (DC) vaccines have been shown to stimulate tumor antigen-specific CD8+ T cells; however, this strategy has demonstrated variable clinical efficacy likely due to immune escape mechanisms that can induce tumor-specific CD8+ T cell dysfunction. Herein, we evaluated the functional characteristics of DC vaccine-induced CD8+ T cells with regard to immune checkpoint inhibitors in gastric cancer patients who were administered Wilms tumor protein-1 (WT1)-targeted DC vaccine. We observed the upregulation of the inhibitory molecule, TIGIT and the inhibitory T cell co-receptors PD1 and Tim3 in limiting WT1-specific CD8+ T cell growth and function in GC patients. TIGIT-expressing PD1+Tim3- CD8+ T cells were the largest subset, while TIGIT+PD1+Tim3+ was the most dysfunctional subset of WT1-specific CD8+ T cells in gastric cancer patients. Importantly, the co-inhibition of TIGIT, PD1, and Tim3 pathways enhanced the growth, proliferation, and cytokine production of WT1-specific CD8+ T cells. In conclusion, our data suggests that targeting TIGIT, PD1, and Tim3 pathways may be important in reversing immune escape in patients with advanced gastric cancer.

Author Info: (1) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (2) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (3) Department of Gastroenterology, Beijing

Author Info: (1) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (2) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (3) Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University China. (4) Key Laboratory of Digestive System Tumors, Second Hospital of Lanzhou University China. (5) Department of Oncology, Beijing Anzhen Hospital Affiliated to The Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases China. (6) Department of Biotherapy Center, Gansu Provincial Hospital China. (7) Department of Hemotology, Gansu Provincial Hospital China. (8) Department of Biochemistry and Molecular Biology, Hainan Medical College China. (9) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (10) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (11) Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.

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Oncolytic Newcastle disease virus induces autophagy-dependent immunogenic cell death in lung cancer cells

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In addition to direct oncolysis, oncolytic viruses trigger immunogenic cell death (ICD) and primes antitumor immunity. We have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW), induces apoptosis and/or autophagy in cancer cells. In this study, we investigated whether oncolytic NDV can induce ICD in lung cancer cells and whether apoptosis or autophagy plays a role in NDV-triggered ICD. To this end, we examined cell surface expression of calreticulin (CRT) on NDV-infected lung cancer cells and measured ICD determinants, high mobility group box 1 (HMGB1), heat shock protein 70/90 (HSP70/90) and ATP in supernatants following viral infection. Flow cytometric analysis using anti-CRT antibody and PI staining of NDV-infected lung cancer cells showed an increase in the number of viable (propidium iodide-negative) cells, suggesting the induction of CRT exposure upon NDV infection. In addition, confocal and immunoblot analysis using anti-CRT antibody showed that an enhanced accumulation of CRT on the cell surface of NDV-infected cells, indicating the translocation of CRT to the cell membrane upon NDV infection. We further demonstrated that NDV infection induced the release of secreted HMGB1 and HSP70/90 by examining the concentrated supernatants of NDV-infected cells. Furthermore, pre-treatment with either the pan-caspase inhibitor z-VAD-FMK or the necrosis inhibitor Necrostain-1, had no impact on NDV-induced release of ICD determinants in lung cancer cells. Rather, depletion of autophagy-related genes in lung cancer cells significantly inhibited the induction of ICD determinants by NDV. Of translational importance, in a lung cancer xenograft model, treatment of mice with supernatants from NDV-infected cells significantly inhibited tumour growth. Together, these results indicate that oncolytic NDV is a potent ICD-inducer and that autophagy contributes to NDV-mediated induction of ICD in lung cancer cells.

Author Info: (1) Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China. Central Laboratory, Cancer Hospital of China Medical University

Author Info: (1) Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China. Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China. Institute of Cancer Stem Cell, Dalian Medical University Dalian, China. (2) Institute of Cancer Stem Cell, Dalian Medical University Dalian, China. (3) Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China. (4) Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences St. James's Hospital & Trinity College Dublin Dublin, Ireland. (5) Department of Oncology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China. Tongji University Cancer Center Shanghai, China. Department of Oncology, Dermatology Hospital, Tongji University Shanghai, China. (6) Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China. (7) Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science Shanghai, China. (8) Institute of Cancer Stem Cell, Dalian Medical University Dalian, China. (9) Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China.

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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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