Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells

Abstract

Chronic inflammation is a complex process that promotes carcinogenesis and tumor progression; however, the mechanisms by which specific inflammatory mediators contribute to tumor growth remain unclear. We and others recently demonstrated that the inflammatory mediators IL-1β, IL-6, and PGE2 induce accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing individuals. MDSC impair tumor immunity and thereby facilitate carcinogenesis and tumor progression by inhibiting T and NK cell activation, and by polarizing immunity toward a tumor-promoting type 2 phenotype. We now show that this population of immature myeloid cells induced by a given tumor share a common phenotype regardless of their in vivo location (bone marrow, spleen, blood, or tumor site), and that Gr1highCD11bhighF4/80−CD80+IL4Rα+/−Arginase+ MDSC are induced by the proinflammatory proteins S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-κB pathway, and promote MDSC migration. MDSC also synthesize and secrete S100A8/A9 proteins that accumulate in the serum of tumor-bearing mice, and in vivo blocking of S100A8/A9 binding to MDSC using an anti-carboxylated glycan Ab reduces MDSC levels in blood and secondary lymphoid organs in mice with metastatic disease. Therefore, the S100 family of inflammatory mediators serves as an autocrine feedback loop that sustains accumulation of MDSC. Since S100A8/A9 activation of MDSC is through the NF-κB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients.

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

“…Interestingly, tumor-induced up-regulation of S100a8 and S100a9 proteins was found in myeloid precursor cells and contributes to the recruitment and accumulation of myeloid-derived suppressor cells at sites of tumor formation. 30,31 Myeloid-derived suppressor cells facilitate carcinogenesis and tumor progression by suppression of T cell and NK cell activation, thereby inhibiting antitumor immunity. 32 Consequently, S100a9-deficient mice mounted a potent antitumor immune response leading to efficient rejection of implanted tumors.…”

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

“…pp , 0.05, relative to any other group. it is possible that the attenuated expression of iNOS, Arg-1, S100A8, and S100A9 transcripts in CD11b + Gr-1 + cells compared with MDSCs might be correlated to the immunostimulatory functions of CD11b + Gr-1 + cells from ID8/ascites (38,39). The mechanisms governing induction of immunostimulatory CD11b + Gr-1 + cells versus MDSCs, are still unknown.…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…Moreover, inflammatory proteins S100A8 and S100A9 produced by MDSCs have been reported to induce the activation of MAPK and NF-κB signaling pathways in tumor cells, enhancing thereby their growth and metastatic potential [86,97]. Together with discussed above MDSC-mediated suppression of anti-tumor T-cell reactivity, the ability of these myeloid cells to stimulate directly tumor growth underlines an important role of the neutralization of MDSC functions for the development of more efficient tumor immunotherapies.…”