IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
artículos
Título:
Targeting TMEM176b enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation
Autor/es:
SEGOVIA, MERCEDES; MAHMOUD, JAMIL; RUSSO, SOFIA; CHAMET, PIERRE; JELDRES, MATHIAS; PEREZ, VALENTINA; VEIGAS,FLORENCIA; M DUHALDE,; ROUSSET, MATHIEU; FLOTO, RA; VICTORIA, SABINA; LOUVET, CEDRIC; GIROTTI, MR; VANHOVE, B; ANEGON, I; SEGOVIA, MERCEDES; CUTURI, MARÍA CRISTINA; RABINOVICH, GABRIEL; MAHMOUD, JAMIL; HILL, MARCELO; RUSSO, SOFIA; JELDRES, MATHIAS; CHAMET, PIERRE; PEREZ, VALENTINA; VEIGAS,FLORENCIA; ROUSSET, MATHIEU; M DUHALDE,; LOUVET, CEDRIC; FLOTO, RA; VICTORIA, SABINA; ANEGON, I; VANHOVE, B; GIROTTI, MR; RABINOVICH, GABRIEL; CUTURI, MARÍA CRISTINA; HILL, MARCELO
Revista:
CANCER CELL
Editorial:
CELL PRESS
Referencias:
Lugar: United States; Año: 2019 p. 767 - 781
ISSN:
1535-6108
Resumen:
Although immune checkpoint blockers have yielded significant clinical benefits in patientswith different malignancies, the efficacy of these therapies is still limited prompting theidentification of novel immunotherapeutic targets. Here, we show that disruptionof Transmembrane Protein 176b (Tmem176b)/Tolerance-Related and Induced cationtransporter (Torid) contributes to CD8+ T cell-mediated tumor growth inhibition byunleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activityof anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1 activation.Accordingly, patients responding to checkpoint blockade therapies display an activatedinflammasome signature. Finally, we identify BayK8644 as a potent Tmem176b inhibitorthat promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity ofboth anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of theinflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immunecheckpoint blockers.