title: Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2.
abstract: It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-β, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α-induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α-mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-β, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Baihua
authors.initials: B
authors.lastname: Li
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Wan
authors.forename: Guohong
authors.initials: G
authors.lastname: Lin
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
authors.forename: Bingjiao
authors.initials: B
authors.lastname: Yin
authors.forename: Zhuoya
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics; D001483:Base Sequence; D004790:Enzyme Induction; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012995:Solubility; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase