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Abstract:

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.

Registro:

Documento: Artículo
Título:Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
Autor: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.
Filiación:Área Investigación, Instituto de Oncología Ángel H. Roffo, Universidad de Buenos Aires, Buenos Aires, C1427, Argentina
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, C1428, Argentina
Facultad de Ciencias Exactas Y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428, Argentina
Palabras clave: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
Año:2015
Volumen:194
Número:7
Página de inicio:3452
Página de fin:3462
DOI: http://dx.doi.org/10.4049/jimmunol.1401144
Título revista:Journal of Immunology
Título revista abreviado:J. Immunol.
ISSN:00221767
CODEN:JOIMA
CAS:arginase, 9000-96-8; indometacin, 53-86-1, 74252-25-8, 7681-54-1; nitric oxide, 10102-43-9; Anti-Inflammatory Agents, Non-Steroidal; Indomethacin; Nitric Oxide; Reactive Oxygen Species
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00221767_v194_n7_p3452_Blidner

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Citas:

---------- APA ----------
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. (2015) . Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments. Journal of Immunology, 194(7), 3452-3462.
http://dx.doi.org/10.4049/jimmunol.1401144
---------- CHICAGO ----------
Blidner, A.G., Salatino, M., Mascanfroni, I.D., Diament, M.J., De Kier Joffé, E.B., Jasnis, M.A., et al. "Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments" . Journal of Immunology 194, no. 7 (2015) : 3452-3462.
http://dx.doi.org/10.4049/jimmunol.1401144
---------- MLA ----------
Blidner, A.G., Salatino, M., Mascanfroni, I.D., Diament, M.J., De Kier Joffé, E.B., Jasnis, M.A., et al. "Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments" . Journal of Immunology, vol. 194, no. 7, 2015, pp. 3452-3462.
http://dx.doi.org/10.4049/jimmunol.1401144
---------- VANCOUVER ----------
Blidner, A.G., Salatino, M., Mascanfroni, I.D., Diament, M.J., De Kier Joffé, E.B., Jasnis, M.A., et al. Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments. J. Immunol. 2015;194(7):3452-3462.
http://dx.doi.org/10.4049/jimmunol.1401144