Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells.
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-1beta, IL-6, and PGE(2) 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 Gr1(high)CD11b(high)F4/80(-)CD80(+)IL4Ralpha(+/-)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-kappaB 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-kappaB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients.
Sinha
Pratima
P
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
Okoro
Chinonyerem
C
Foell
Dirk
D
Freeze
Hudson H
HH
Ostrand-Rosenberg
Suzanne
S
Srikrishna
Geetha
G
D000818:Animals; D019046:Bone Marrow Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D040501:Calgranulin A / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D040502:Calgranulin B / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013160:Splenic Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary
D040501:Calgranulin A; D040502:Calgranulin B; D018836:Inflammation Mediators
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