4 research outputs found
PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
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