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Cancer Cell. 2019 May 13;35(5):767-781.e6. doi: 10.1016/j.ccell.2019.04.003.

Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.

Author information

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.
3
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.
4
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France.
5
INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France.
6
INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France; Xenothera, 44093 Nantes, France.
7
Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, UK.
8
INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France. Electronic address: ccuturi@nantes.inserm.fr.
9
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.
10
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.

Abstract

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.

KEYWORDS:

TMEM176B; cancer; dendritic cells; immune checkpoint blockers; inflammasome; ion channel

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