Inhibition of ATR downregulates PD-L1 and sensitizes tumor cells to T cell-mediated killing.
Inhibition of ATR downregulates PD-L1 and sensitizes tumor cells to T cell-mediated killing.
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发表时间：
2018
影响因子：
5.3
通讯作者：
Lin-lin Sun;Riyao Yang;Chia‐Wei Li;Mei-Kuang Chen;B. Shao;J. Hsu;Li-Chuan Chan;Yi Yang;J. Hsu-J
中科院分区：
文献类型：
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作者：
Lin-lin Sun;Riyao Yang;Chia‐Wei Li;Mei-Kuang Chen;B. Shao;J. Hsu;Li-Chuan Chan;Yi Yang;J. Hsu-J
共济失调毛细血管扩张和Rad 3相关（ATR）激酶在维持基因组稳定性以应对DNA损伤中起着至关重要的作用。一旦被激活，ATR通过其下游靶点起作用，以阻止细胞周期，促进DNA修复，并提高细胞存活率。因此，ATR已成为肿瘤治疗中一个有吸引力的治疗靶点。多项临床研究表明，ATR抑制剂可使癌细胞对常规DNA损伤剂敏感。然而，ATR抑制剂对肿瘤微环境中免疫应答的潜在影响，特别是对免疫检查点相关蛋白表达的影响，仍然是难以捉摸的。在这里，我们表明，DNA损伤剂，如电离辐射和顺铂，显着诱导细胞表面PD-L1在各种癌细胞类型的表达。这种作用被ATR的消耗或药理学抑制所阻断，表明ATR在DNA损伤诱导的PD-L1表达中的重要作用。从机制上讲，我们表明ATR的破坏以蛋白酶体依赖的方式使PD-L1不稳定。此外，临床ATR激酶抑制剂下调PD-L1表达以减弱PD-L1/PD-1相互作用并使癌细胞对T细胞杀伤敏感。总的来说，我们的研究结果表明，除了增强DNA损伤外，ATR抑制剂同时下调PD-L1水平并增强抗肿瘤免疫应答。此外，我们的数据揭示了DNA损伤反应信号传导和免疫检查点之间的潜在串扰，为ATR抑制剂和免疫检查点阻断的联合治疗提供了理论基础。
The ataxia telangiectasia and Rad3-related (ATR) kinase plays a crucial role in maintaining genome stability in response to DNA damage. Once activated, ATR acts via its downstream target to arrest the cell cycle, promote DNA repair, and enhance cell survival. Therefore, ATR has become an attractive therapeutic target in cancer therapy. Multiple clinical studies have demonstrated that ATR inhibitors can sensitize cancer cells to conventional DNA damaging agents. However, the potential effects of ATR inhibitors on immune response in the tumor microenvironment, especially on the expression of immune checkpoint-related proteins, remain elusive. Here we show that DNA damaging agents, such as ionizing radiation and cisplatin, significantly induce cell surface PD-L1 expression in various cancer cell types. This effect is blocked by depletion or pharmacological inhibition of ATR, suggesting the essential role of ATR in DNA damage-induced PD-L1 expression. Mechanistically, we show that disruption of ATR destabilizes PD-L1 in a proteasome-dependent manner. Furthermore, clinical ATR kinase inhibitor downregulates PD-L1 expression to attenuate PD-L1/PD-1 interaction and sensitize cancer cells to T cell killing. Collectively, our findings indicate that in addition to potentiating DNA damage, ATR inhibitor concurrently downregulates PD-L1 levels and enhances anti-tumor immune responses. Moreover, our data reveal a potential crosstalk between DNA damage response signaling and immune checkpoints, providing a rationale for the combination therapy of ATR inhibitor and immune checkpoint blockade.