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

Mercedes Segovia (1, 2) , Sofia Russo (1, 2) , Mathias Jeldres (1) , Yamil D Mahmoud (3) , Valentina Perez (1, 2) , Maite Duhalde (1) , Pierre Charnet (4) , Matthieu Rousset (4) , Sabina Victoria (1) , Florencia Veigas (3) , Cédric Louvet (5) , Bernard Vanhove (5, 6) , R. Andrés Floto (7) , Ignacio Anegon (8) , Maria Cristina Cuturi (9) , M. Romina Girotti (3) , Gabriel A. Rabinovich (3, 10) , Marcelo Hill (1, 2)

1 Immunoregulation and Inflamation / Inmunoregulación e Inflamación [Montevideo]
2 Department of Immunobiology [Montevideo, Uruguay]
3 Laboratories of Immunopathology and Translational Immuno-Oncology [Buenos Aires, Argentina]
4 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
5 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
6 Xenothera [Nantes, France]
7 Department of Medicine - Molecular Immunity Unit [Cambridge, UK]
8 Team 2 - U1064 Inserm - CRTI - Genetic and Cellular Engineering in Immunology and Regenerative Medicine
9 Team 1 - U1064 Inserm - CRTI - Dendritic cells and immunoregulation in transplantation and immunopathology
10 School of Exact and Natural Sciences - Department of Biological Chemistry [Buenos Aires, Argentina]

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.

Mots clés: dendritic cells; cancer; TMEM176B; immune checkpoint blockers; inflammasome; ion channel

Domaines: Médecine humaine et pathologie

Mercedes Segovia, Sofia Russo, Mathias Jeldres, Yamil D Mahmoud, Valentina Perez, et al.. Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation. Cancer Cell, 2019, 35 (5), pp.767-781. ⟨10.1016/j.ccell.2019.04.003⟩. ⟨inserm-02145714⟩