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

Autores
Blidner, Ada Gabriela; Salatino, Mariana; Mascanfroni, Ivan Darío; Diament, Miriam; Bal, Elisa Dora; Maria A. Jasnis; Slobodanka M. Klein; Rabinovich, Gabriel Adrián
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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-â 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
Fil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Diament, Miriam. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Maria A. Jasnis. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Slobodanka M. Klein. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Materia
Mdsc
Indometacin
Lung Cancer Cells
Tumor Microenvironment
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/45016
Acceder
id CONICETDig_e84ce4805a9c65761205c120f462cf43
oai_identifier_str oai:ri.conicet.gov.ar:11336/45016
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironmentsBlidner, Ada GabrielaSalatino, MarianaMascanfroni, Ivan DaríoDiament, MiriamBal, Elisa DoraMaria A. JasnisSlobodanka M. KleinRabinovich, Gabriel AdriánMdscIndometacinLung Cancer CellsTumor Microenvironmenthttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Myeloid-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-â 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 autoimmunityFil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Diament, Miriam. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Maria A. Jasnis. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Slobodanka M. Klein. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaAmerican Association of Immunologists2015-04-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/45016Blidner, Ada Gabriela; Salatino, Mariana; Mascanfroni, Ivan Darío; Diament, Miriam; Bal, Elisa Dora; et al.; Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments; American Association of Immunologists; Journal of Immunology; 194; 7; 1-4-2015; 3452-34620022-1767CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jimmunol.org/content/194/7/3452.longinfo:eu-repo/semantics/altIdentifier/doi//10.4049/jimmunol.1401144info:eu-repo/semantics/altIdentifier/pmid/25740944info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:35:20Zoai:ri.conicet.gov.ar:11336/45016instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:35:20.531CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
title Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
spellingShingle Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments
Blidner, Ada Gabriela
Mdsc
Indometacin
Lung Cancer Cells
Tumor Microenvironment
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
dc.creator.none.fl_str_mv Blidner, Ada Gabriela
Salatino, Mariana
Mascanfroni, Ivan Darío
Diament, Miriam
Bal, Elisa Dora
Maria A. Jasnis
Slobodanka M. Klein
Rabinovich, Gabriel Adrián
author Blidner, Ada Gabriela
author_facet Blidner, Ada Gabriela
Salatino, Mariana
Mascanfroni, Ivan Darío
Diament, Miriam
Bal, Elisa Dora
Maria A. Jasnis
Slobodanka M. Klein
Rabinovich, Gabriel Adrián
author_role author
author2 Salatino, Mariana
Mascanfroni, Ivan Darío
Diament, Miriam
Bal, Elisa Dora
Maria A. Jasnis
Slobodanka M. Klein
Rabinovich, Gabriel Adrián
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mdsc
Indometacin
Lung Cancer Cells
Tumor Microenvironment
topic Mdsc
Indometacin
Lung Cancer Cells
Tumor Microenvironment
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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-â 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
Fil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Diament, Miriam. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Maria A. Jasnis. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Slobodanka M. Klein. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
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-â 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
publishDate 2015
dc.date.none.fl_str_mv 2015-04-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/45016
Blidner, Ada Gabriela; Salatino, Mariana; Mascanfroni, Ivan Darío; Diament, Miriam; Bal, Elisa Dora; et al.; Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments; American Association of Immunologists; Journal of Immunology; 194; 7; 1-4-2015; 3452-3462
0022-1767
CONICET Digital
CONICET
url http://hdl.handle.net/11336/45016
identifier_str_mv Blidner, Ada Gabriela; Salatino, Mariana; Mascanfroni, Ivan Darío; Diament, Miriam; Bal, Elisa Dora; et al.; Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments; American Association of Immunologists; Journal of Immunology; 194; 7; 1-4-2015; 3452-3462
0022-1767
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jimmunol.org/content/194/7/3452.long
info:eu-repo/semantics/altIdentifier/doi//10.4049/jimmunol.1401144
info:eu-repo/semantics/altIdentifier/pmid/25740944
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association of Immunologists
publisher.none.fl_str_mv American Association of Immunologists
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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