The "Inside" Story on Tumor-Expressed PD-L1.
While the extracellular domain of PD-L1 is well-recognized for playing a critical role in immune evasion by suppressing CD8+ T-cell activity through direct PD-1 interactions, a series of studies has evolved highlighting important functional roles for the PD-L1 cytoplasmic domain in supporting various aspects of tumorigenesis. Kornepati and colleagues contribute to our overall understanding of PD-L1 in tumor biology by describing a link between tumor PD-L1 expression and DNA repair. These studies demonstrate that PD-L1 promotes breast cancer type 1 (BRCA1)-mediated homologous recombination while inhibiting cytosolic DNA sensing, thus suppressing tumor immunogenicity. Notably, these effects could not be reversed with anti-PD-L1 antibodies utilized in the clinic, suggesting that pharmacologic agents promoting PD-L1 degradation may be a more effective treatment strategy for select tumors. Studies that are improving our understanding of the pathways driven by PD-L1 cytoplasmic signaling are providing increased insight into the design of next generation combinatorial immunotherapy strategies. See related article by Kornepati et al., p. 2156.
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