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• W2994602105 abstract "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." @default.
• W2994602105 created "2019-12-13" @default.
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• W2994602105 date "2018-01-01" @default.
• W2994602105 modified "2023-10-14" @default.
• W2994602105 title "Inhibition of ATR downregulates PD-L1 and sensitizes tumor cells to T cell-mediated killing." @default.
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• W2994602105 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6079156" @default.
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