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.
Highlights
Tumor growth implies a systemic state of immune suppression, characterized by bone marrow (BM) expansion and circulation of myeloid cells able to suppress adaptive immune responses through a variety of mechanisms [1, 2]
Immune cells express the ITIMreceptor LAIR-1 that binds to Gly-Pro-Hyp collagen conserved motives [20]. The triggering of this receptor activates a negative inhibitory signal that blocks cell activation including neutrophil extracellular traps (NET) formation and reactive oxygen species (ROS) production [21, 22] We have recently demonstrated that an aberrant extracellular matrix (ECM) deposition characterized by secreted protein acidic and rich in cysteine (SPARC) and high collagen content promotes the recruitment of suppressive myeloid cells [23]
We found that high-grade breast cancer (BC) patients have a significantly increased frequency of earlystage MDSC (eMDSC) if compared to healthy donors (HD) (Figure 1A and Supplementary Figure 1A for gating strategy)
Summary
Tumor growth implies a systemic state of immune suppression, characterized by bone marrow (BM) expansion and circulation of myeloid cells able to suppress adaptive immune responses through a variety of mechanisms [1, 2]. The so-called myeloid-derived suppressor cells (MDSC) are a heterogeneous pool of myeloid cells, mainly composed by two subsets, the monocytic (M)-MDSC and the polymorphonuclear (PMN)MDSC, characterized by different phenotypic markers, which are distinct between human and mouse. The two subsets expand differently and are endowed with different suppressive activities depending on the specific tumor types [3, 4]. Once in the TME, MDSC acquire suppressive activity through the chronic sensing of inflammatory cytokines and damage-associated molecular patterns (DAMP). PMN-MDSC are phenotypically almost indistinguishable from neutrophils, which share several functions in favor of tumor growth and dissemination. M-MDSC are instead similar to monocytes and are characterized by high plasticity: in the TME they can differentiate in macrophages and dendritic cells [7, 8]
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