IFN-γ activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation

• DOI: 10.1080/2162402x.2022.2044103
• Publication Date: 2022-03-03T14:59:56Z
• Authors: Hui Xiong; Yu Xi; Zhiwei Yuan; Boyu Wang; Shaojie Hu; Can Fang; Yixin Cai; Xiangning Fu; Lequn Li
• Keywords: Lung Neoplasms; Programmed Cell Death 1 Receptor; Adenocarcinoma of Lung; B7-H1 Antigen; Interferon-gamma; 03 medical and health sciences; Tumor Microenvironment; Humans; IFN-γ; RC254-282; Original Research; 0303 health sciences; T cell activation; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Membrane Proteins; DNA; DNA, Neoplasm; Interferon-beta; RC581-607; lung adenocarcinoma; 3. Good health; DNA damage; Immunologic diseases. Allergy; STING; DNA Damage; Signal Transduction

Stimulator of interferon genes (STING) pathway activation predicts the effectiveness of targeting the PD-1/PD-L1 axis in lung cancer. Active IFN-γ signaling is a common feature in tumors that respond to PD-1/PD-L1 blockade. The connection between IFN-γ and STING signaling in cancer cells has not been documented. We showed that IFN-γ caused DNA damage and the accumulation of cytosolic dsDNA, leading to the activation of the cGAS- and IFI16-dependent STING pathway in lung adenocarcinoma cells. IFN-γ-induced iNOS expression and nitric oxide production were responsible for DNA damage and STING activation. Additional etoposide treatment enhanced IFN-γ-induced IFN-β and CCL5 expression. Tumor-infiltrating T cells stimulated with a combination of anti-CD3 and anti-PD-1 antibodies caused STING activation and increased IFN-β and CCL5 expression in lung adenocarcinoma. These effects were abrogated by the addition of an IFN-γ neutralizing antibody. Our results suggest that the activation of tumor-infiltrating T cells could alter the tumor microenvironment via the IFN-γ-mediated activation of STING signaling in cancer cells.