PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
Maria Gato-Cañas 1 , Miren Zuazo 1 , Hugo Arasanz 2 , Maria Ibañez-Vea 1 , Laura Lorenzo 1 , Gonzalo Fernandez-Hinojal 2 , Ruth Vera 3 , Cristian Smerdou 4 , Eva Martisova 4 , Imanol Arozarena 1 , Claudia Wellbrock 5 , Diana Llopiz 4 , Marta Ruiz 4 , Pablo Sarobe 4 , Karine Breckpot 6 , Grazyna Kochan 7 , David Escors 8
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.
CITA DEL ARTÍCULO Cell Rep. 2017 Aug 22;20(8):1818-1829. doi: 10.1016/j.celrep.2017.07.075