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- Title
ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation.
- 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.
- Abstract
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.
- Subjects
ATAXIA telangiectasia; DNA damage; T cell differentiation; ANTINEOPLASTIC agents; NON-small-cell lung carcinoma
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 9, p3926
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI96519