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

Lisa A. Ridnour, Robert Y.S. Cheng, Noemi Kedei, Veena Somasundaram, Dibyangana D. Bhattacharyya, Debashree Basudhar, Adelaide L. Wink, Abigail J. Walke, Caleb Kim, William F. Heinz, Elijah F. Edmondson, Donna O. Butcher, Andrew C. Warner, Tiffany H. Dorsey, Milind Pore, Robert J. Kinders, Stanley Lipkowitz, Richard J. Bryant, Jens Rittscher, Stephen T.C. WongStephen M. Hewitt, Jenny C. Chang, Aliaa Shalaby, Grace M. Callagy, Sharon A. Glynn, Stefan Ambs, Stephen K. Anderson, Daniel W. McVicar, Stephen J. Lockett, David A. Wink

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere165356
JournalJCI insight
Volume9
Issue number12
DOIs
StatePublished - Jun 24 2024

Keywords

  • Animals
  • Membrane Proteins/metabolism
  • Mice
  • Female
  • Signal Transduction/drug effects
  • T-Lymphocytes, Cytotoxic/immunology
  • Triple Negative Breast Neoplasms/pathology
  • Indomethacin/pharmacology
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms/immunology
  • Cyclooxygenase Inhibitors/pharmacology
  • Nucleotidyltransferases/metabolism
  • Interferon Type I/metabolism
  • Cyclooxygenase 2/metabolism
  • Lymphocytes, Tumor-Infiltrating/immunology
  • Mice, Inbred BALB C

ASJC Scopus subject areas

  • General Medicine

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