Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors

• Published in: JCI insight Vol. 9; no. 12
• Main Authors: Ridnour, Lisa A, Cheng, Robert Ys, Kedei, Noemi, Somasundaram, Veena, Bhattacharyya, Dibyangana D, Basudhar, Debashree, Wink, Adelaide L, Walke, Abigail J, Kim, Caleb, Heinz, William F, Edmondson, Elijah F, Butcher, Donna O, Warner, Andrew C, Dorsey, Tiffany H, Pore, Milind, Kinders, Robert J, Lipkowitz, Stanley, Bryant, Richard J, Rittscher, Jens, Wong, Stephen Tc, Hewitt, Stephen M, Chang, Jenny C, Shalaby, Aliaa, Callagy, Grace M, Glynn, Sharon A, Ambs, Stefan, Anderson, Stephen K, McVicar, Daniel W, Lockett, Stephen J, Wink, David A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 21-05-2024
• Subjects: Animals; Cell Line, Tumor; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Female; Humans; Indomethacin - pharmacology; Indomethacin - therapeutic use; Interferon Type I - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Nucleotidyltransferases - metabolism; Signal Transduction - drug effects; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - radiotherapy; Oncology; Adaptive immunity; Breast cancer; Inflammation
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.165356

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.