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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3926-3940
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number9
DOIs
StatePublished - Aug 31 2018

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Phosphotransferases
Radiation
T-Lymphocytes
Radiotherapy
Neoplasms
Immunologic Memory
Drug Therapy
DNA
Radiation Effects
Immunosuppressive Agents
Head and Neck Neoplasms
Non-Small Cell Lung Carcinoma
Immunotherapy
DNA Damage
Melanoma
Up-Regulation
Ligands
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Vendetti, F. P., Karukonda, P., Clump, D. A., Teo, T., Lalonde, R., Nugent, K., ... Bakkenist, C. J. (2018). ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. Journal of Clinical Investigation, 128(9), 3926-3940. https://doi.org/10.1172/JCI96519

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

In: Journal of Clinical Investigation, Vol. 128, No. 9, 31.08.2018, p. 3926-3940.

Research output: Contribution to journalArticle

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 2018, 'ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation', Journal of Clinical Investigation, vol. 128, no. 9, pp. 3926-3940. https://doi.org/10.1172/JCI96519
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. / ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 9. pp. 3926-3940.
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