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SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we s...

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Autores principales: Sangaletti, Sabina, Talarico, Giovanna, Chiodoni, Claudia, Cappetti, Barbara, Botti, Laura, Portararo, Paola, Gulino, Alessandro, Consonni, Francesca Maria, Sica, Antonio, Randon, Giovanni, Di Nicola, Massimo, Tripodo, Claudio, Colombo, Mario P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596449/
https://www.ncbi.nlm.nih.gov/pubmed/31281314
http://dx.doi.org/10.3389/fimmu.2019.01369
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author Sangaletti, Sabina
Talarico, Giovanna
Chiodoni, Claudia
Cappetti, Barbara
Botti, Laura
Portararo, Paola
Gulino, Alessandro
Consonni, Francesca Maria
Sica, Antonio
Randon, Giovanni
Di Nicola, Massimo
Tripodo, Claudio
Colombo, Mario P.
author_facet Sangaletti, Sabina
Talarico, Giovanna
Chiodoni, Claudia
Cappetti, Barbara
Botti, Laura
Portararo, Paola
Gulino, Alessandro
Consonni, Francesca Maria
Sica, Antonio
Randon, Giovanni
Di Nicola, Massimo
Tripodo, Claudio
Colombo, Mario P.
author_sort Sangaletti, Sabina
collection PubMed
description Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc(−/−) MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc(−/−) MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc(−/−) than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc(−/−) MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc(−/−) MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway.
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spelling pubmed-65964492019-07-05 SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities Sangaletti, Sabina Talarico, Giovanna Chiodoni, Claudia Cappetti, Barbara Botti, Laura Portararo, Paola Gulino, Alessandro Consonni, Francesca Maria Sica, Antonio Randon, Giovanni Di Nicola, Massimo Tripodo, Claudio Colombo, Mario P. Front Immunol Immunology Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc(−/−) MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc(−/−) MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc(−/−) than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc(−/−) MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc(−/−) MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway. Frontiers Media S.A. 2019-06-20 /pmc/articles/PMC6596449/ /pubmed/31281314 http://dx.doi.org/10.3389/fimmu.2019.01369 Text en Copyright © 2019 Sangaletti, Talarico, Chiodoni, Cappetti, Botti, Portararo, Gulino, Consonni, Sica, Randon, Di Nicola, Tripodo and Colombo. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Sangaletti, Sabina
Talarico, Giovanna
Chiodoni, Claudia
Cappetti, Barbara
Botti, Laura
Portararo, Paola
Gulino, Alessandro
Consonni, Francesca Maria
Sica, Antonio
Randon, Giovanni
Di Nicola, Massimo
Tripodo, Claudio
Colombo, Mario P.
SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities
title SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities
title_full SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities
title_fullStr SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities
title_full_unstemmed SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities
title_short SPARC Is a New Myeloid-Derived Suppressor Cell Marker Licensing Suppressive Activities
title_sort sparc is a new myeloid-derived suppressor cell marker licensing suppressive activities
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596449/
https://www.ncbi.nlm.nih.gov/pubmed/31281314
http://dx.doi.org/10.3389/fimmu.2019.01369
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