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

Accepted version
Peer-reviewed

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Authors

Segovia, Mercedes 
Russo, Sofia 
Jeldres, Mathias 
Mahmoud, Yamil D 
Perez, Valentina 

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.

Description

Keywords

TMEM176B, cancer, dendritic cells, immune checkpoint blockers, inflammasome, ion channel, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Animals, Antibodies, Monoclonal, Antineoplastic Agents, CD8-Positive T-Lymphocytes, CHO Cells, Cell Line, Cell Line, Tumor, Cell Proliferation, Cricetulus, Female, Humans, Inflammasomes, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Xenopus laevis

Journal Title

Cancer Cell

Conference Name

Journal ISSN

1535-6108
1878-3686

Volume Title

35

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (107032/Z/15/Z)
Uruguay INNOVA 2, Fondo Maria Viñas and Clemente Estable from ANII, as well as grants from CABBIO, PEDECIBA, ECOS-SUD and FOCEM (MERCOSUR Structural Convergence Fund), COF 03/11 to MH, The Harry J Lloyd Foundation to MRG and the Instituto Nacional del Cancer to YDM, Agencia de Promoción Científica y Tecnológica to GAR and MRG, Fundación Bunge & Born and Fundación Sales to GAR