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

By P. Sinha, C. Okoro, D. Foell, H. Freeze, S. Ostrand-Rosenberg, G. Srikrishna. Journal of Immunology, 2008

740 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d3d637add20d0a7c0df6f851b2d7b55d828ab641

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Molecular Biology

Citations in the corpus

Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer (2009, background): “they chemoattract MDSC to tumor sites through a NF- B-dependent pathway (29).”
Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function (2010, background): “These receptors signal the effects of S100A9 and S100A8 through activation of the NF-κB pathway [36].”
The nature of myeloid-derived suppressor cells in the tumor microenvironment (2016, result): “Changes in the myeloid compartment in cancer are evident in BM, since accumulation of MDSC in BM of tumor-bearing hosts was reported in many studies [7–9].”
Functions of S100 Proteins (2012, background): “Human S100A8/S100A9 is chemotactic for neutrophils [209] and influences migration of other cell types, including myeloid-derived suppressor cells [245] and some tumor cells [174], and may facilitate tumor cell invasion [246,247] (Fig.”
Tumor‐associated macrophages (TAM) as major players of the cancer‐related inflammation (2009, background): “Among other factors, S-100 proteins, proinflammatory factors present at the tumor site, strongly attract MDSCs, and interestingly, this process is also sustained by an autocrine loop, as MDSCs secrete these proteins themselves [120].”