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ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation

DNA damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between Programmed Death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small lung cancer (NSCLC), melanoma, and head and neck squamous cell carcinoma (HNSCC). ATR is a DNA damage signaling kinase activated at damaged replication forks and ATR kinase inhibitors potentiate the cytotoxicity of DNA damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating T regulatory (Treg) cells. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the exciting possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.

Vendetti FP, Karukonda P, Clump DA, Teo T, Lalonde R, Nugent K, Ballew M, Kiesel BF, Beumer JH, Sarkar SN, Conrads TP, O’Connor MJ, Ferris RL, Tran PT, Delgoffe GM, Bakkenist CJ.

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