Inhibition of ATR downregulates PD-L1 and sensitizes tumor cells to T cell-mediated killing

American Journal of Cancer Research

Bin Shao¹  Jung-Mao Hsu²  Ri-Yao Yang³  Li-Chuan Chan⁴  Mei-Kuang Chen⁵  Chia-Wei Li⁶  Lin-Lin Sun⁷ 

[1] Department of Biotechnology, Asia University, Taichung 413, Taiwan;Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital Institute, Beijing, P. R. China;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan;Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA;Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 30052, P. R. China

关键词: Cancer biology;    DNA damage response;    protein kinase;    immune checkpoint;    protein degradation;    ATR;    immunotherapy;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

CC BY-NC