Segovia et al. show that the transmembrane protein 176B (TMEM176B) suppresses antitumor immunity by reducing the accumulation of cytosolic Ca2+ within DCs and macrophages, which prevents activation of the NLRP3 inflammasome and the release of activated (cleaved) caspase-1. Thus, IL-1β and pro-IL-18 cannot be processed into their active, pro-inflammatory forms. Tmem176b-/- mice showed increased CD8+ T cell infiltration into tumors and improved responses to checkpoint blockades; BayK8644 was found to inhibit TMEM176B and recapitulate these effects. An inflammasome-activated signature was identified in patients responding to anti-PD-1.
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-1beta 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.
Author Info: (1) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay; Immunobiology Department, Faculty of Medicine, University of the Rep
Author Info: (1) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay; Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay. (2) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay; Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay. (3) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay. (4) Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina. (5) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay; Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay. (6) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay. (7) Institut des Biomolecules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Universite de Montpellier, 34093 Montpellier, France. (8) Institut des Biomolecules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Universite de Montpellier, 34093 Montpellier, France. (9) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay. (10) Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina. (11) INSERM UMR 1064, Center for Research in Transplantation and Immunology, Universite de Nantes, CHU Nantes, Institut de Transplantation Urologie Nephrologie (ITUN), 44093 Nantes, France. (12) INSERM UMR 1064, Center for Research in Transplantation and Immunology, Universite de Nantes, CHU Nantes, Institut de Transplantation Urologie Nephrologie (ITUN), 44093 Nantes, France; Xenothera, 44093 Nantes, France. (13) Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, UK. (14) INSERM UMR 1064, Center for Research in Transplantation and Immunology, Universite de Nantes, CHU Nantes, Institut de Transplantation Urologie Nephrologie (ITUN), 44093 Nantes, France. (15) INSERM UMR 1064, Center for Research in Transplantation and Immunology, Universite de Nantes, CHU Nantes, Institut de Transplantation Urologie Nephrologie (ITUN), 44093 Nantes, France. Electronic address: ccuturi@nantes.inserm.fr. (16) Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina. (17) Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina; Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina. (18) Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay; Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay. Electronic address: mhill@pasteur.edu.uy.
