A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2
A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2
复制标题
肿瘤特异性超级增强子通过引导 PD-L1 和 PD-L2 的同步表达来驱动免疫逃避。
DOI：
10.1016/j.celrep.2019.10.093
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发表时间：
2019-12-10
期刊：
影响因子：
8.8
通讯作者：
Fan, Yihui
中科院分区：
文献类型：
--
作者：
Xu, Yuanpei;Wu, Yingcheng;Fan, Yihui
PD-L1和PD-L2是免疫检查点阻断的重要靶点，但肿瘤细胞如何实现其表达仍有待解决。在这里，我们发现PD-L1和PD-L2在不同癌症类型的癌细胞系和组织中共表达。在乳腺癌中，MDA-MB-231和SUM-159细胞显示PD-L1和PDL 2的高表达。PD-L1和PD-L2的表达在超级增强子的抑制剂处理后大大降低。生物信息学分析鉴定了位于CD 274和CD 273基因之间的潜在超级增强子（PD-L1 L2-SE）。PD-L1 L2-SE的遗传缺失显著降低了PD-L1和PD-L2的表达。PD-L1 L2-SE缺陷型癌细胞不能产生免疫逃避，并且对T细胞介导的杀伤敏感。值得注意的是，这种区域（PD-L1 L2-SE）的表观遗传活化与PD-L1和PD-L2相关。综上所述，我们确定了一种超级增强子（PDL 1 L2-SE），它负责PD-L1和PD-L2的过表达以及癌症中的免疫逃避。
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.