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XB-ART-56701
Cancer Cell January 1, 2019; 35 (5): 767-781.e6.

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

Segovia M , Russo S , Jeldres M , Mahmoud YD , Perez V , Duhalde M , Charnet P , Rousset M , Victoria S , Veigas F , Louvet C , Vanhove B , Floto RA , Anegon I , Cuturi MC , Girotti MR , Rabinovich GA , Hill M .


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.

PubMed ID: 31085177
PMC ID: PMC6521897
Article link: Cancer Cell
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: b3gat1l casp1 cd4 ctla4 foxp3 il1b il6 itgam myh4 myh6 rho slc22a6
GO keywords: ion channel activity [+]

Disease Ontology terms: cancer

Article Images: [+] show captions
References [+] :
Binnewies, Understanding the tumor immune microenvironment (TIME) for effective therapy. 2019, Pubmed