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

Autor: Ridnour LA; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Cheng RY; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Kedei N; Collaborative Protein Technology Resource (CPTR) Nanoscale Protein Analysis, OSTR, CCR, NCI, NIH, Bethesda, Maryland, USA., Somasundaram V; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Bhattacharyya DD; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Basudhar D; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Wink AL; Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, and., Walke AJ; Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, and., Kim C; Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, and., Heinz WF; Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, and., Edmondson EF; Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, Maryland, USA., Butcher DO; Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, Maryland, USA., Warner AC; Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, Maryland, USA., Dorsey TH; Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, Maryland, USA., Pore M; Imaging Mass Cytometry Frederick National Laboratory for Cancer Research, and., Kinders RJ; Office of the Director, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, Maryland, USA., Lipkowitz S; Women's Malignancy Branch CCR, NCI, NIH, Bethesda, Maryland, USA., Bryant RJ; Department of Urology, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom., Rittscher J; Institute of Biomedical Engineering, Big Data Institute, Ludwig Oxford Branch, University of Oxford, Oxford, United Kingdom., Wong ST; Houston Methodist Neal Cancer Center, Weill Cornell Medical College, Houston Methodist Hospital, Houston, Texas, USA., Hewitt SM; Laboratory of Pathology CCR, NCI, NIH, Bethesda, Maryland, USA., Chang JC; Houston Methodist Neal Cancer Center, Weill Cornell Medical College, Houston Methodist Hospital, Houston, Texas, USA., Shalaby A; Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, Ireland., Callagy GM; Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, Ireland., Glynn SA; Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, Ireland., Ambs S; Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, Maryland, USA., Anderson SK; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA.; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., McVicar DW; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA., Lockett SJ; Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, and., Wink DA; Cancer Innovation Laboratory, CCR, NCI, NIH, Frederick, Maryland, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 May 21; Vol. 9 (12). Date of Electronic Publication: 2024 May 21.
DOI: 10.1172/jci.insight.165356
Abstrakt: 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.
Databáze: MEDLINE