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Transmembrane TNF-alpha promotes suppressive activities of myeloid-derived suppressor cells via TNFR2 #MMPMID24379122
Hu X; Li B; Li X; Zhao X; Wan L; Lin G; Yu M; Wang J; Jiang X; Feng W; Qin Z; Yin B; Li Z
J Immunol 2014[Feb]; 192 (3): 1320-31 PMID24379122show ga
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-alpha (tmTNF-alpha) is the primary ligand for TNFR2, we hypothesized that tmTNF-alpha is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-alpha, rather than secretory TNF-alpha (sTNF-alpha), 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-beta, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-alpha was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-alpha-induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-alpha caused p38 phosphorylation and NF-kappaB activation, whereas inhibition of NF-kappaB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-alpha-mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-alpha 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-beta, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-alpha mutant by 4T1 cells that only released sTNF-alpha without expression of surface tmTNF-alpha markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-alpha acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.
J+Immunol 2014 ; 192 (3): 1320-31
