SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Sabina Sangaletti, Giovanna Talarico, Claudia Chiodoni, Barbara Cappetti, Laura Botti, Paola Portararo, Alessandro Gulino, Francesca Maria Consonni, Antonio Sica, Giovanni Randon, Massimo Di Nicola, Claudio Tripodo, Mario P. Colombo

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number1369
JournalFrontiers in Immunology
Volume10
Issue numberJUN
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Licensure
Cysteine
Proteins
Epithelial-Mesenchymal Transition
NF-kappa B
Myeloid-Derived Suppressor Cells
Neoplasms
Inflammation
Arginase
Tumor Microenvironment
Immunosuppressive Agents
Tumor Biomarkers
Flow Cytometry
Phosphorylation
Phenotype

Keywords

  • Breast cancer
  • Myeloid-derived suppressor cells
  • Neutrophil
  • Neutrophil extracellular traps
  • SPARC

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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; Nicola, Massimo Di; Tripodo, Claudio; Colombo, Mario P.

In: Frontiers in Immunology, Vol. 10, No. JUN, 1369, 01.01.2019.

Research output: Contribution to journalArticle

Sangaletti, Sabina ; Talarico, Giovanna ; Chiodoni, Claudia ; Cappetti, Barbara ; Botti, Laura ; Portararo, Paola ; Gulino, Alessandro ; Consonni, Francesca Maria ; Sica, Antonio ; Randon, Giovanni ; Nicola, Massimo Di ; Tripodo, Claudio ; Colombo, Mario P. / SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities. In: Frontiers in Immunology. 2019 ; Vol. 10, No. JUN.
@article{c1056035438643f08772762d64831cee,
title = "SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities",
abstract = "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.",
keywords = "Breast cancer, Myeloid-derived suppressor cells, Neutrophil, Neutrophil extracellular traps, SPARC",
author = "Sabina Sangaletti and Giovanna Talarico and Claudia Chiodoni and Barbara Cappetti and Laura Botti and Paola Portararo and Alessandro Gulino and Consonni, {Francesca Maria} and Antonio Sica and Giovanni Randon and Nicola, {Massimo Di} and Claudio Tripodo and Colombo, {Mario P.}",
year = "2019",
month = "1",
day = "1",
doi = "10.3389/fimmu.2019.01369",
language = "English",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",
number = "JUN",

}

TY - JOUR

T1 - SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

AU - Sangaletti, Sabina

AU - Talarico, Giovanna

AU - Chiodoni, Claudia

AU - Cappetti, Barbara

AU - Botti, Laura

AU - Portararo, Paola

AU - Gulino, Alessandro

AU - Consonni, Francesca Maria

AU - Sica, Antonio

AU - Randon, Giovanni

AU - Nicola, Massimo Di

AU - Tripodo, Claudio

AU - Colombo, Mario P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Myeloid-derived suppressor cells

KW - Neutrophil

KW - Neutrophil extracellular traps

KW - SPARC

UR - http://www.scopus.com/inward/record.url?scp=85069218394&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069218394&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2019.01369

DO - 10.3389/fimmu.2019.01369

M3 - Article

C2 - 31281314

AN - SCOPUS:85069218394

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - JUN

M1 - 1369

ER -