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

• Published in: Cancer cell 2019-05, Vol.35 (5), p.767-781.e6
• Main Authors: Segovia, Mercedes, Russo, Sofia, Jeldres, Mathias, Mahmoud, Yamil D., Perez, Valentina, Duhalde, Maite, Charnet, Pierre, Rousset, Matthieu, Victoria, Sabina, Veigas, Florencia, Louvet, Cédric, Vanhove, Bernard, Floto, R. Andrés, Anegon, Ignacio, Cuturi, Maria Cristina, Girotti, M. Romina, Rabinovich, Gabriel A., Hill, Marcelo
• Format: Article
• Language: English
• Subjects: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; cancer; CD8-Positive T-Lymphocytes - drug effects; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; CHO Cells; Cricetulus; dendritic cells; Female; Human health and pathology; Humans; immune checkpoint blockers; inflammasome; Inflammasomes - drug effects; Inflammasomes - immunology; ion channel; Life Sciences; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; TMEM176B; Xenopus laevis - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2019.04.003

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. [Display omitted] •TMEM176B inhibits the NLRP3 inflammasome by controlling cytosolic Ca2+.•Lack of Tmem176b enhances antitumor immunity via the caspase-1/IL-1β pathway•Human tumors responding to immune checkpoint blockade display an inflammasome-activated signature•A TMEM176B inhibitor improves the antitumor activity of immune checkpoint blockade Segovia et al. show that TMEM176B inhibits inflammasome activation and IL-1β cleavage by controlling cytosolic Ca2+ in dendritic cells and macrophages. Inhibition of TMEM176B enhances tumor infiltration by CD8+ T cells and improves the antitumor activity of immune checkpoint blockers.