Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.
Cuturi, Maria Cristina
Girotti, M Romina
Rabinovich, Gabriel A
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Segovia, M., Russo, S., Jeldres, M., Mahmoud, Y. D., Perez, V., Duhalde, M., Charnet, P., et al. (2019). Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.. Cancer cell, 35 (5), 767-781.e6. https://doi.org/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 prompting the identification of novel immunotherapeutic targets. Here, we show that disruption of Transmembrane Protein 176b (Tmem176b)/Tolerance-Related and Induced cation transporter (Torid) 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-1 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.
CD8-Positive T-Lymphocytes, Cell Line, Cell Line, Tumor, CHO Cells, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Xenopus laevis, Humans, Cricetulus, Mice, Neoplasms, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Membrane Proteins, Antineoplastic Agents, Antibodies, Monoclonal, Cell Proliferation, Female, Male, Inflammasomes
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
WELLCOME TRUST (107032/Z/15/Z)
External DOI: https://doi.org/10.1016/j.ccell.2019.04.003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292626
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/