Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation
Copyright policy )Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation
Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
- Institut de Chimie France
- Institut des Biomolécules Max Mousseron France
- University of Cambridge United Kingdom
- University of Buenos Aires Argentina
- Institut National de la Santé et la Recherche Médicale France
Cancer Immunoediting, Male, Inflammasomes, CD8-Positive T-Lymphocytes, Inflammasome, Mice, Xenopus laevis, https://purl.org/becyt/ford/1.6, Neoplasms, https://purl.org/becyt/ford/3.1, Tumor Microenvironment, Internal medicine, Immunology and Microbiology, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Life Sciences, Antibodies, Monoclonal, CANCER, ION CHANNEL, immune checkpoint blockers, Oncology, Medicine, Biomarkers for Immunotherapy, Female, Immune checkpoint, Immunotherapy, TMEM176B, Receptor, Molecular Mechanisms of Inflammasome Activation and Regulation, Innate Immunity to Viral Infection, Immunology, 610, Antineoplastic Agents, Cancer research, CHO Cells, DENDRITIC CELLS, Article, Cancer Immunotherapy, Cell Line, Cricetulus, inflammasome, Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, 616, Health Sciences, cancer, Animals, Humans, https://purl.org/becyt/ford/3, dendritic cells, https://purl.org/becyt/ford/1, Molecular Biology, Biology, Antibody, Cell Proliferation, Pharmacology, Inflammation, FOS: Clinical medicine, T cell, Membrane Proteins, CD8, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Immune Checkpoint Blockade, Blockade, Mice, Inbred C57BL, Immune system, INFLAMMASOME, IMMUNE CHECKPOINT BLOCKERS, ion channel, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Cancer Immunoediting, Male, Inflammasomes, CD8-Positive T-Lymphocytes, Inflammasome, Mice, Xenopus laevis, https://purl.org/becyt/ford/1.6, Neoplasms, https://purl.org/becyt/ford/3.1, Tumor Microenvironment, Internal medicine, Immunology and Microbiology, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Life Sciences, Antibodies, Monoclonal, CANCER, ION CHANNEL, immune checkpoint blockers, Oncology, Medicine, Biomarkers for Immunotherapy, Female, Immune checkpoint, Immunotherapy, TMEM176B, Receptor, Molecular Mechanisms of Inflammasome Activation and Regulation, Innate Immunity to Viral Infection, Immunology, 610, Antineoplastic Agents, Cancer research, CHO Cells, DENDRITIC CELLS, Article, Cancer Immunotherapy, Cell Line, Cricetulus, inflammasome, Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, 616, Health Sciences, cancer, Animals, Humans, https://purl.org/becyt/ford/3, dendritic cells, https://purl.org/becyt/ford/1, Molecular Biology, Biology, Antibody, Cell Proliferation, Pharmacology, Inflammation, FOS: Clinical medicine, T cell, Membrane Proteins, CD8, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Immune Checkpoint Blockade, Blockade, Mice, Inbred C57BL, Immune system, INFLAMMASOME, IMMUNE CHECKPOINT BLOCKERS, ion channel, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
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