Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments

Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study,...

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Autores principales:	Blidner, A.G., Salatino, M., Mascanfroni, I.D., Diament, M.J., De Kier Joffé, E.B., Jasnis, M.A., Klein, S.M., Rabinovich, G.A.
Formato:	JOUR
Materias:	arginase indometacin nitric oxide reactive oxygen metabolite nonsteroid antiinflammatory agent animal cell animal experiment animal model animal tissue antiinflammatory activity antineoplastic activity Article bone marrow cell cancer inhibition CD8+ T lymphocyte cell differentiation cellular parameters controlled study correlational study enzyme activity female immune deficiency lung adenocarcinoma mouse nonhuman priority journal protein expression suppressor cell tumor free microenvironment tumor microenvironment tumor volume animal autoimmunity biological model disease model drug effects experimental autoimmune encephalomyelitis immunology immunophenotyping metabolism neoplasm pathology phenotype signal transduction T lymphocyte subpopulation Animals Anti-Inflammatory Agents, Non-Steroidal Autoimmunity Cellular Microenvironment Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental Female Immunophenotyping Indomethacin Mice Models, Biological Myeloid Cells Neoplasms Nitric Oxide Phenotype Reactive Oxygen Species Signal Transduction T-Lymphocyte Subsets Tumor Burden Tumor Microenvironment
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00221767_v194_n7_p3452_Blidner
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_00221767_v194_n7_p3452_Blidner2023-10-03T14:27:59Z Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments Blidner, A.G. Salatino, M. Mascanfroni, I.D. Diament, M.J. De Kier Joffé, E.B. Jasnis, M.A. Klein, S.M. Rabinovich, G.A. arginase indometacin nitric oxide reactive oxygen metabolite indometacin nitric oxide nonsteroid antiinflammatory agent reactive oxygen metabolite animal cell animal experiment animal model animal tissue antiinflammatory activity antineoplastic activity Article bone marrow cell cancer inhibition CD8+ T lymphocyte cell differentiation cellular parameters controlled study correlational study enzyme activity female immune deficiency lung adenocarcinoma mouse nonhuman priority journal protein expression suppressor cell tumor free microenvironment tumor microenvironment tumor volume animal autoimmunity biological model bone marrow cell disease model drug effects experimental autoimmune encephalomyelitis immunology immunophenotyping metabolism neoplasm pathology phenotype signal transduction T lymphocyte subpopulation tumor microenvironment Animals Anti-Inflammatory Agents, Non-Steroidal Autoimmunity Cellular Microenvironment Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental Female Immunophenotyping Indomethacin Mice Models, Biological Myeloid Cells Neoplasms Nitric Oxide Phenotype Reactive Oxygen Species Signal Transduction T-Lymphocyte Subsets Tumor Burden Tumor Microenvironment Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8+ T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-β transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity. Copyright © 2015 by The American Association of Immunologists, Inc. Fil:Salatino, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Jasnis, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00221767_v194_n7_p3452_Blidner
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	arginase indometacin nitric oxide reactive oxygen metabolite indometacin nitric oxide nonsteroid antiinflammatory agent reactive oxygen metabolite animal cell animal experiment animal model animal tissue antiinflammatory activity antineoplastic activity Article bone marrow cell cancer inhibition CD8+ T lymphocyte cell differentiation cellular parameters controlled study correlational study enzyme activity female immune deficiency lung adenocarcinoma mouse nonhuman priority journal protein expression suppressor cell tumor free microenvironment tumor microenvironment tumor volume animal autoimmunity biological model bone marrow cell disease model drug effects experimental autoimmune encephalomyelitis immunology immunophenotyping metabolism neoplasm pathology phenotype signal transduction T lymphocyte subpopulation tumor microenvironment Animals Anti-Inflammatory Agents, Non-Steroidal Autoimmunity Cellular Microenvironment Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental Female Immunophenotyping Indomethacin Mice Models, Biological Myeloid Cells Neoplasms Nitric Oxide Phenotype Reactive Oxygen Species Signal Transduction T-Lymphocyte Subsets Tumor Burden Tumor Microenvironment
spellingShingle	arginase indometacin nitric oxide reactive oxygen metabolite indometacin nitric oxide nonsteroid antiinflammatory agent reactive oxygen metabolite animal cell animal experiment animal model animal tissue antiinflammatory activity antineoplastic activity Article bone marrow cell cancer inhibition CD8+ T lymphocyte cell differentiation cellular parameters controlled study correlational study enzyme activity female immune deficiency lung adenocarcinoma mouse nonhuman priority journal protein expression suppressor cell tumor free microenvironment tumor microenvironment tumor volume animal autoimmunity biological model bone marrow cell disease model drug effects experimental autoimmune encephalomyelitis immunology immunophenotyping metabolism neoplasm pathology phenotype signal transduction T lymphocyte subpopulation tumor microenvironment Animals Anti-Inflammatory Agents, Non-Steroidal Autoimmunity Cellular Microenvironment Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental Female Immunophenotyping Indomethacin Mice Models, Biological Myeloid Cells Neoplasms Nitric Oxide Phenotype Reactive Oxygen Species Signal Transduction T-Lymphocyte Subsets Tumor Burden Tumor Microenvironment Blidner, A.G. Salatino, M. Mascanfroni, I.D. Diament, M.J. De Kier Joffé, E.B. Jasnis, M.A. Klein, S.M. Rabinovich, G.A. Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
topic_facet	arginase indometacin nitric oxide reactive oxygen metabolite indometacin nitric oxide nonsteroid antiinflammatory agent reactive oxygen metabolite animal cell animal experiment animal model animal tissue antiinflammatory activity antineoplastic activity Article bone marrow cell cancer inhibition CD8+ T lymphocyte cell differentiation cellular parameters controlled study correlational study enzyme activity female immune deficiency lung adenocarcinoma mouse nonhuman priority journal protein expression suppressor cell tumor free microenvironment tumor microenvironment tumor volume animal autoimmunity biological model bone marrow cell disease model drug effects experimental autoimmune encephalomyelitis immunology immunophenotyping metabolism neoplasm pathology phenotype signal transduction T lymphocyte subpopulation tumor microenvironment Animals Anti-Inflammatory Agents, Non-Steroidal Autoimmunity Cellular Microenvironment Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental Female Immunophenotyping Indomethacin Mice Models, Biological Myeloid Cells Neoplasms Nitric Oxide Phenotype Reactive Oxygen Species Signal Transduction T-Lymphocyte Subsets Tumor Burden Tumor Microenvironment
description	Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8+ T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-β transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity. Copyright © 2015 by The American Association of Immunologists, Inc.
format	JOUR
author	Blidner, A.G. Salatino, M. Mascanfroni, I.D. Diament, M.J. De Kier Joffé, E.B. Jasnis, M.A. Klein, S.M. Rabinovich, G.A.
author_facet	Blidner, A.G. Salatino, M. Mascanfroni, I.D. Diament, M.J. De Kier Joffé, E.B. Jasnis, M.A. Klein, S.M. Rabinovich, G.A.
author_sort	Blidner, A.G.
title	Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
title_short	Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
title_full	Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
title_fullStr	Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
title_full_unstemmed	Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
title_sort	differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
url	http://hdl.handle.net/20.500.12110/paper_00221767_v194_n7_p3452_Blidner
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Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments

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