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.

Duke Scholars

Author Brent A. Hanks Medicine, Medical Oncology