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.
Keywords:
Cancer; Immunology; Oncology.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma of Lung / drug therapy
-
Adenocarcinoma of Lung / immunology
-
Adenocarcinoma of Lung / radiotherapy
-
Animals
-
Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
-
B7-H1 Antigen / metabolism
-
CD8-Positive T-Lymphocytes / drug effects*
-
CD8-Positive T-Lymphocytes / immunology
-
CD8-Positive T-Lymphocytes / radiation effects*
-
Cell Line, Tumor
-
Chemoradiotherapy
-
Colorectal Neoplasms / drug therapy
-
Colorectal Neoplasms / immunology
-
Colorectal Neoplasms / radiotherapy
-
Humans
-
Indoles
-
Lymphocytes, Tumor-Infiltrating / drug effects
-
Lymphocytes, Tumor-Infiltrating / immunology
-
Lymphocytes, Tumor-Infiltrating / radiation effects
-
Mice
-
Mice, Inbred BALB C
-
Morpholines
-
Neoplasms, Experimental / drug therapy*
-
Neoplasms, Experimental / immunology
-
Neoplasms, Experimental / radiotherapy*
-
Protein Kinase Inhibitors / pharmacokinetics
-
Protein Kinase Inhibitors / pharmacology*
-
Proto-Oncogene Proteins p21(ras) / genetics
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology*
-
Radiotherapy, Conformal
-
Sulfonamides
-
Sulfoxides / pharmacokinetics
-
Sulfoxides / pharmacology*
Substances
-
B7-H1 Antigen
-
Cd274 protein, mouse
-
Indoles
-
Morpholines
-
Protein Kinase Inhibitors
-
Pyrimidines
-
Sulfonamides
-
Sulfoxides
-
ceralasertib
-
Atr protein, mouse
-
Ataxia Telangiectasia Mutated Proteins
-
Hras protein, mouse
-
Proto-Oncogene Proteins p21(ras)