BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.

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Abstrakt

Tytuł:: BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.
Autorzy:: Lombardo KA; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Greenberg Bladder Cancer Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Obradovic A; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
Singh AK; Center for Tuberculosis Research, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Liu JL; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Joice G; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Kates M; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Bishai W; Center for Tuberculosis Research, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
McConkey D; Greenberg Bladder Cancer Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Chaux A; Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción, Paraguay.
Eich ML; Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Rezaei MK; Department of Pathology, George Washington University, Washington, DC, USA.
Netto GJ; Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Drake CG; Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Division of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.; Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
Tran P; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Department of Radiation Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Matoso A; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Greenberg Bladder Cancer Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Bivalacqua TJ; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Greenberg Bladder Cancer Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Źródło:: The Journal of pathology [J Pathol] 2022 Feb; Vol. 256 (2), pp. 223-234. Date of Electronic Publication: 2021 Dec 10.
Typ publikacji:: Comparative Study; Journal Article; Research Support, N.I.H., Extramural
Język:: English
Imprint Name(s):: Publication: Chichester : John Wiley And Sons
Original Publication: London, Oliver & Boyd.
MeSH Terms:: Immunotherapy*
Radiation Dosage*
Antineoplastic Agents/*administration & dosage
BCG Vaccine/*administration & dosage
Immunity, Innate/*drug effects
Immunity, Innate/*radiation effects
Membrane Proteins/*immunology
Urinary Bladder Neoplasms/*therapy
Urothelium/*drug effects
Urothelium/*radiation effects
Administration, Intravesical ; Animals ; Female ; Humans ; Inflammation Mediators/metabolism ; Lymphocytes, Tumor-Infiltrating/drug effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/radiation effects ; Membrane Proteins/metabolism ; Mice, Inbred C57BL ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/radiation effects ; Tumor Microenvironment/immunology ; Tumor-Associated Macrophages/drug effects ; Tumor-Associated Macrophages/immunology ; Tumor-Associated Macrophages/metabolism ; Tumor-Associated Macrophages/radiation effects ; Urinary Bladder Neoplasms/immunology ; Urinary Bladder Neoplasms/metabolism ; Urinary Bladder Neoplasms/pathology ; Urothelium/immunology ; Urothelium/metabolism ; Mice
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Grant Information:: F30 CA260765 United States CA NCI NIH HHS; R01 AI155346 United States AI NIAID NIH HHS
Contributed Indexing:: Keywords: BCG; STING; T-cells; Trex-1; bladder cancer; innate immunity; interferon; macrophages; radiotherapy; tumor immune microenvironment
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (BCG Vaccine)
0 (Inflammation Mediators)
0 (Membrane Proteins)
0 (STING1 protein, human)
0 (Sting1 protein, mouse)
Entry Date(s):: Date Created: 20211103 Date Completed: 20220221 Latest Revision: 20240226
Update Code:: 20240226
PubMed Central ID:: PMC8738146
DOI:: 10.1002/path.5830
PMID:: 34731491
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Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 10 8 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland.
(© 2021 The Pathological Society of Great Britain and Ireland.)

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