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. Spar c −/− 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 Spar c −/− 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 Spar c −/− 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 Spar c −/− 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 Spar c −/− 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.

The Engagement Between MDSCs and Metastases: Partners in Crime

“…Recently, Sangaletti and collaborators demonstrated that impaired translocation of NF-κB p50 protein abolishes the secretion of protein acidic and rich in cysteine (SPARC) and alters MDSC-associated immunosuppression by limiting ROS production. Indeed, restricted p50 translocation into nucleus limits the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers that sustain an increased release of TNFα in the tumor microenvironment (47). According to this, we demonstrated that, the enhancement of nuclear p50 translocation by c-FLIP promotes acquisition of immunosuppressive function by monocytes (42).…”

“…The MDSC plasticity and functions are strictly guided by the activation of precise signaling pathways [extensively reviewed in (8,45)] preferentially driven by c/EBPβ (CCAAT/enhancerbinding protein) (16), STAT3 (signal transducer and activator of transcription 3) (31,46) and NF-κB (42,47) transcriptional factors. c/EBPβ is the master regulator of "emergency" myelopoiesis and its critical role on MDSC biology was proved using myeloid-restricted c/EBPβ-deficient mice engrafted with different tumor models in which the ontogeny and MDSCassociated immunosuppression were completely abrogated (16).…”

“…In light of these evidences, it is not surprising that SPARC, a matricellular protein produced by tumor cells, promotes the expansion and recruitment of MDSCs (120). In turn, the ablation of SPARC in PMN-MDSCs reduces their suppressive activity and their capacity to sustain EMT and tumor growth (47). Similarly, silencing osteopotin (OPN), a matrix protein, in 4T1 breast cancer cells prevents metastasis development by affecting M-MDSC suppressive activity but not their recruitment at the metastatic site (121).…”

Crosstalk between Tumor Cells and Immune System Leads to Epithelial-Mesenchymal Transition Induction and Breast Cancer Progression

“…SPARC and CXCR2 are two factors expressed in MDSCs and required for the acquisition of MDSC suppressive phenotype [62,64,65] . MDSC differentiation is facilitated by the tumor-derived cytokines, including G-CSF, GM-CSF, VEGF, and chemokines such as CCL2 and CXCL12 [62,[66][67][68][69] . Moreover, Thrombospondin 1 expression in the surface of MDSC-derived exosomes also causes MDSCs chemotaxis and migration [64] .…”

SPARC regulation of PMN clearance protects from pristane induced lupus and rheumatoid arthritis

“…Some divergent functions of SPARC reveal its complexity and underscore the context dependency of its activity, which strictly depends on tissue and cellular origin (Bradshaw, 2012). A under-investigated but interesting aspect of SPARC function, is the capacity of regulating the immune system in several aspects, such as dendritic cell migration and branching (Piconese et al, 2011), myeloidderived suppressor cell expansion and functional differentiation (Sangaletti et al, 2019) and B cell development (Luo et al, 2014;Sangaletti et al, 2014a). Studying mesenchymal cells functions in bone-marrow (BM) and secondary lymphoid organs we showed that the defective B cells development occurring in Sparc -/hosts under radiation-induced stress relies on SPARC limiting B cells precursors apoptosis (Sangaletti et al, 2014a).…”