A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2

PD-L1 and PD-L2 are important targets for immune checkpoint blockade, but how tumor cells achieve their expression remains to be addressed. Here, we find that PD-L1 and PD-L2 are co-expressed in cancer cell lines and tissues across different cancer types. In breast cancer, MDA-MB-231 and SUM-159 cells show high expression of both PD-L1 and PDL2. The expression of both PD-L1 and PD-L2 is greatly reduced upon treatment of inhibitors of super-enhancers. Bioinformatic analysis identifies a potential super-enhancer (PD-L1L2-SE) that is located between the CD274 and CD273 genes. Genetic deletion of PD-L1L2-SE profoundly reduces the expression of PD-L1 and PD-L2. PD-L1L2-SEdeficient cancer cells fail to generate immune evasion and are sensitive to T cell-mediated killing. Notably, epigenetic activation of such a region (PD-L1L2-SE) is correlated with PD-L1 and PD-L2. Taken together, we identify a super-enhancer (PDL1L2-SE) that is responsible for the overexpression of PD-L1 and PD-L2 as well as immune evasion in cancer.