ATR Inhibition Potentiates the Radiation-induced Inflammatory Tumor Microenvironment

Area of Science:

• Oncology
• Immunology
• Radiation Oncology

Background:

• ATR inhibitors (ATRi) show preclinical promise in sensitizing tumors to chemotherapy and radiotherapy.
• Limited data exist on the impact of ATRi on the tumor microenvironment.
• HPV-driven malignancies represent a significant clinical challenge.

Purpose of the Study:

• To investigate the effects of the ATR inhibitor AZD6738 in combination with fractionated radiation (RT) on HPV-driven malignancies.
• To analyze the impact of ATRi + RT on the tumor microenvironment and immune cell infiltration.
• To elucidate the underlying molecular mechanisms of the observed radiosensitization.

Main Methods:

• Utilized an immunocompetent mouse model of HPV-driven malignancies.
• Administered AZD6738 in combination with fractionated radiation therapy.
• Performed gene expression analysis and flow cytometry post-therapy to assess immune cell infiltration and molecular changes.

Main Results:

• Significant radiosensitization was observed with ATRi + RT, accompanied by increased immune cell infiltration, including CD3+, NK, and myeloid cells.
• A type I/II interferon (IFN) response signature was identified, with upregulation of nucleic acid-sensing pathway genes.
• Increased MHC Class I levels on tumor cells and enhanced antigen processing/presentation were noted, alongside modulated cytokine expression (CCL2, CCL5, CXCL10).

Conclusions:

• DNA damage induced by ATRi + RT activates IFN responses via nucleic acid-sensing pathways.
• This activation promotes increased antigen presentation and innate immune cell infiltration.
• Understanding this combination's immunomodulatory effects could optimize tumor control strategies through enhanced antitumor immunity.