%0 Journal Article
%T ATR kinase inhibitor AZD6738 potentiates CD8+ T cell¨Cdependent antitumor activity following radiation
%A Brian F. Kiesel
%A Christopher J. Bakkenist
%A David A. Clump
%A Frank P. Vendetti
%A Greg M. Delgoffe
%A Jan H. Beumer
%A Katriana Nugent
%A Mark J. O¡¯Connor
%A Matthew Ballew
%A Phuoc T. Tran
%A Pooja Karukonda
%A Robert L. Ferris
%A Ronald Lalonde
%A Saumendra N. Sarkar
%A Thomas P. Conrads
%A Troy Teo
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI96519
%X 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¨Csmall cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage¨Csignaling 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
%U https://www.jci.org/articles/view/96519