Gato Cañas, MaríaZuazo Ibarra, MirenArasanz Esteban, HugoIbañez Vea, MaríaLorenzo, LauraFernández Hinojal, GonzaloVera García, RuthSmerdou, CristianMartisova, EvaArozarena Martinicorena, ImanolWellbrock, ClaudiaLlopiz, DianaRuiz, MartaSarobe, PabloBreckpot, KarineKochan, GrazynaEscors Murugarren, David2022-08-082022-08-082017Gato-Cañas, M.; Ibañez-Vea, M.; Zuazo, M.; Arasanz, H.; Lorenzo, L.; Fernandez-Hinojal, G.; Vera, R.; Smerdou, C.; Martisova, E.; Arozarena, I.; Wellbrock, C.; Llopiz, D.; Ruiz, M.; Sarobe, P.; Breckpot, K.; Kochan, G.; Escors, D.. (2017). PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity. Cell Reports. 20,8, pp. 1818-18292211-124710.1016/j.celrep.2017.07.075https://academica-e.unavarra.es/handle/2454/43728PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.application/pdfeng© 2017 The Authors. This is an open access article under the CC BY-NC-ND licensePDL1PD-L1B7-H1CD274PD1InterferonSignal transductionImmunotherapyinfo:eu-repo/semantics/article2022-08-08info:eu-repo/semantics/openAccess