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

• Main Authors: Yuanpei Xu, Yingcheng Wu, Siliang Zhang, Panpan Ma, Xinxin Jin, Zhou Wang, Min Yao, Erhao Zhang, Baorui Tao, Yongwei Qin, Hao Chen, Aifen Liu, Miaomiao Chen, Mingbing Xiao, Cuihua Lu, Renfang Mao, Yihui Fan
• Format: Article
• Language: English
• Published: Elsevier 2019-12-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719314159

Summary: 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. : 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. Keywords: Immune Checkpoint Blockade, PD-L1, PD-L2, super-enhancers, BRD4, MED1, H3K27Ac, Breast cancer, Immune evasion