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

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.

SUBMITTER: Sun LL

PROVIDER: S-EPMC6079156 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Sun Lin-Lin LL Yang Ri-Yao RY Li Chia-Wei CW Chen Mei-Kuang MK Shao Bin B Hsu Jung-Mao JM Chan Li-Chuan LC Yang Yi Y Hsu Jennifer L JL Lai Yun-Ju YJ Hung Mien-Chie MC

American journal of cancer research 20180701 7

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 ...[more]

PMID: 30094103

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Project description:Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD-1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death-ligand 1 (PD-L1) found on cancer cells. Blocking PD-1/PD-L1 binding improves T-cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD-1/PD-L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti-PD-1/PD-L1 treatment. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) has been recently identified as a major regulator of PD-L1. Another member in the CMTM family, CKLF-like MARVEL transmembrane domain-containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD-L1 in the context of liver cancer. Up-regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD-L1 expression, hence facilitating escape from T cell-mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD-L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD-L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T-cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti-PD-L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti-PD-L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti-PD-L1 immunotherapy in patients with liver cancer.

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

Publications

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

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