3 years ago

PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
David Escors, Cristian Smerdou, Ruth Vera, Grazyna Kochan, Miren Zuazo, Laura Lorenzo, Maria Gato-Cañas, Karine Breckpot, Imanol Arozarena, Hugo Arasanz, Pablo Sarobe, Marta Ruiz, Gonzalo Fernandez-Hinojal, Maria Ibañez-Vea, Eva Martisova, Diana Llopiz, Claudia Wellbrock

Summary

PDL1 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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31068-9

DOI: 10.1016/j.celrep.2017.07.075

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