info:eu-repo/semantics/article
Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
Fecha
2019-05Registro en:
Segovia, Mercedes; Russo, Sofia; Jeldres, Mathias; Mahmoud, Yamil Damián; Perez, Valentina; et al.; Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation; Cell Press; Cancer Cell; 35; 5; 5-2019; 767-781
1535-6108
CONICET Digital
CONICET
Autor
Segovia, Mercedes
Russo, Sofia
Jeldres, Mathias
Mahmoud, Yamil Damián
Perez, Valentina
Duhalde, Maite
Charnet, Pierre
Rousset, Matthieu
Victoria, Sabina
Veigas, Florenci
Louvet, Cédric
Vanhove, Bernard
Floto, R. Andrés
Anegon, Ignacio
Cuturi, Maria Cristina
Girotti, Maria Romina
Rabinovich, Gabriel Adrián
Hill, Marcelo
Resumen
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.