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

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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [36 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02145714
Contributor : Ana Paula Dutra Azevedo <>
Submitted on : Monday, June 3, 2019 - 11:35:42 AM
Last modification on : Tuesday, November 5, 2019 - 1:26:04 PM

File

1-s2.0-S1535610819301989-main ...
Publisher files allowed on an open archive

Identifiers

Citation

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

Share

Metrics

Record views

60

Files downloads

84