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

  1. Author:
    Ridnour,Lisa
    Cheng,Robert
    Kedei, Noemi
    Somasundaram, Veena
    Bhattacharyya, Dibyangana D
    Basudhar, Debashree
    Wink, Adelaide L
    Walke, Abigail J
    Kim,Caleb
    Heinz,Will
    Edmondson,Elijah
    Butcher,Donna
    Warner,Andrew
    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,Steve
    McVicar,Dan
    Lockett,Stephen
    Wink,David

  2. Author Address

    Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Collaborative Protein Technology Resource (CPTR) Nanoscale Protein Analysis, OSTR, CCR, NCI, NIH, Bethesda, Maryland, USA., Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, and., Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, Maryland, USA., Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, Maryland, USA., Imaging Mass Cytometry Frederick National Laboratory for Cancer Research, and., Office of the Director, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, Maryland, USA., Women 39;s Malignancy Branch CCR, NCI, NIH, Bethesda, Maryland, USA., Department of Urology, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom., Institute of Biomedical Engineering, Big Data Institute, Ludwig Oxford Branch, University of Oxford, Oxford, United Kingdom., Houston Methodist Neal Cancer Center, Weill Cornell Medical College, Houston Methodist Hospital, Houston, Texas, USA., Laboratory of Pathology CCR, NCI, NIH, Bethesda, Maryland, USA., Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, Ireland., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.,
    1. Year: 2024
    2. Date: May 21
    3. Epub Date: 2024 05 21
  2. Journal: JCI Insight
    1. 9
    2. 12
  4. Type of Article: Article
  5. Article Number: e165356
  1. 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.

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External Sources

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  2. DOI: 10.1172/jci.insight.165356
  3. PMID: 38912586
  4. PII : 165356

Library Notes

  1. Fiscal Year: FY2023-2024
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