Targeting TORID-1 enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation

Published: 20-11-2018| Version 1 | DOI: 10.17632/gvj6fc2b8v.1
Contributors:
Mercedes Segovia,
Sofia Russo,
Marcelo Hill

Description

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 TOlerance-Related and InduceD cation transporter-1 (Torid-1/Tmem176b), contributes to CD8+ T-cell mediated tumor rejection by unleashing NLPR3 inflammasome activation. Lack of Torid-1 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 Torid-1 inhibitor that promotes CD8+ T-cell-mediated tumor rejection and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the NLRP3 inflammasome by targeting Torid-1 may enhance the therapeutic efficacy of immune checkpoint blockers.

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