ATR Inhibition Potentiates the Radiation-induced Inflammatory Tumor Microenvironment.
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Authors
Dillon, MT
Bergerhoff, KF
Pedersen, M
Whittock, H
Crespo-Rodriguez, E
Patin, EC
Pearson, A
Smith, HG
Paget, JTE
Patel, RR
Foo, S
Bozhanova, G
Ragulan, C
Fontana, E
Desai, K
Wilkins, AC
Sadanandam, A
Melcher, A
McLaughlin, M
Harrington, KJ
Bergerhoff, KF
Pedersen, M
Whittock, H
Crespo-Rodriguez, E
Patin, EC
Pearson, A
Smith, HG
Paget, JTE
Patel, RR
Foo, S
Bozhanova, G
Ragulan, C
Fontana, E
Desai, K
Wilkins, AC
Sadanandam, A
Melcher, A
McLaughlin, M
Harrington, KJ
Document Type
Journal Article
Date
2019-06-01
Date Accepted
2019-02-11
Abstract
PURPOSE: ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these drugs on the tumor microenvironment.Experimental Design: We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed posttherapy. RESULTS: Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3+ and NK cells, but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II IFN response, with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5, and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5, and CXCL10 are produced from tumor cells after ATRi + RT. CONCLUSIONS: We show that DNA damage by ATRi and RT leads to an IFN response through activation of nucleic acid-sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximize tumor control through antitumor immunity.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (11), pp. 3392 - 3403
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Research Team
Systems and Precision Cancer Medicine
Targeted Therapy
Translational Immunotherapy
Targeted Therapy
Translational Immunotherapy