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

• Published in: The Journal of clinical investigation Vol. 128; no. 9; pp. 3926 - 3940
• Main Authors: Vendetti, Frank P, Karukonda, Pooja, Clump, David A, Teo, Troy, Lalonde, Ronald, Nugent, Katriana, Ballew, Matthew, Kiesel, Brian F, Beumer, Jan H, Sarkar, Saumendra N, Conrads, Thomas P, O'Connor, Mark J, Ferris, Robert L, Tran, Phuoc T, Delgoffe, Greg M, Bakkenist, Christopher J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 31-08-2018
• Subjects: Oncology; Immunology; Cancer
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI96519

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 cell lung cancer, melanoma, and head and neck squamous cell carcinoma. 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 Tregs. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.