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 PD-L2. 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-SE-deficient 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 (PD-L1L2-SE) that is responsible for the overexpression of PD-L1 and PD-L2 as well as immune evasion in cancer. [Display omitted] •Synchronous expression of PD-L1 and PD-L2 is dependent on super-enhancers•The PD-L1L2-SE is a super-enhancer located between the genes encoding PD-L1 and PD-L2•PD-L1L2-SE mediates immune evasion by driving PD-L1 and PD-L2 expression•The activation of PD-L1L2-SE associates with PD-L1 and PD-L2 in cancer patients It is largely unknown how cancer cells achieve the expression of the twin co-inhibitory ligands, PD-L1 and PD-L2. Xu et al. report a super-enhancer called PD-L1L2-SE located between the genes encoding PD-L1 and PD-L2 that can induce immune evasion through synchronously initiating the expression of PD-L1 and PD-L2.