ATR kinase inhibitor AZD6738 potentiates CD8+ T cell–dependent antitumor activity following radiation
Frank P. Vendetti, … , Greg M. Delgoffe, Christopher J. Bakkenist
Frank P. Vendetti, … , Greg M. Delgoffe, Christopher J. Bakkenist
Published June 28, 2018
Citation Information: J Clin Invest. 2018;128(9):3926-3940. https://doi.org/10.1172/JCI96519.
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Research Article Immunology Oncology

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

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.

Authors

Frank P. Vendetti, Pooja Karukonda, David A. Clump, Troy Teo, Ronald Lalonde, Katriana Nugent, Matthew Ballew, Brian F. Kiesel, Jan H. Beumer, Saumendra N. Sarkar, Thomas P. Conrads, Mark J. O’Connor, Robert L. Ferris, Phuoc T. Tran, Greg M. Delgoffe, Christopher J. Bakkenist

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Figure 1

AZD6738 potentiates radiation in syngeneic CT26 tumors and promotes immunologic memory following complete responses.

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AZD6738 potentiates radiation in syngeneic CT26 tumors and promotes immu...
(A) Schematic showing schedules of the ATR kinase inhibitor AZD6738 and targeted radiation (IR). AZD6738 (75 mg/kg) was administered approximately 40 minutes before IR on days 1–2 and alone on day 3. (B and C) Response of CT26 over time to treatment with AZD6738, IR, or the combination of AZD6738 plus IR. Data represent mean tumor volumes ± SEM (B) or individual tumor volumes (C) from 2 independent experiments. n per arm (mice) = 12 vehicle, 10 AZD6738, 12 IR, 14 AZD6738 + IR. **P < 0.01, unpaired, 2-tailed t test comparing change in tumor volume from day 1 to day 20 for AZD6738 + IR vs. IR. Statistical significance not shown for other time points. (D) Complete responses of CT26 tumors over time to treatment with AZD6738 plus IR. (E) Tumor growth following rechallenge of complete responder mice with CT26 cells in the contralateral flank compared with tumor growth in CT26-naive control mice. (D and E) Data represent individual tumor volumes. n per arm (mice) = 4 AZD6738 + IR complete responders, 5 naive controls.