TNF signaling drives myeloid-derived suppressor cell accumulation。 J Clin Invest., October 15, 2012
发布时间：2012-10-24
Journal of Clinical Investigation 2012, doi: 10.1172/JCI64115. Published October 15, 2012
TNF signaling drives myeloid-derived suppressor cell accumulation
Xueqiang Zhao1,2, Lijie Rong1,2, Xiaopu Zhao1,2, Xiao Li1, Xiaoman Liu1, Jingjing Deng1,2, Hao Wu1, Xia Xu1, Ulrike Erben3, Peihua Wu3, Uta Syrbe3, Joachim Sieper3 and Zhihai Qin1
1Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
2Graduate University of the Chinese Academy of Sciences, Beijing, China.3Campus Benjamin Franklin, Charité, Berlin, Germany.
Authorship note: Xueqiang Zhao, Lijie Rong, and Xiaopu Zhao contributed equally to this work.
Abstract
TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted in TNF receptor–deficient (Tnfr–/–) mice are spontaneously rejected; however, the molecular mechanisms underlying this rejection are unclear. Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell–mediated antitumor responses. Peripheral accumulation of MDSCs was drastically impaired in Tnfr–/– mice. Signaling of TNFR-2, but not TNFR-1, promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein (c-FLIP) and inhibition of caspase-8 activity. Loss of TNFRs impaired the induction of MDSCs from bone marrow cells, but this could be reversed by treatment with caspase inhibitors. These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system.
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全文链接：http://www.jci.org/articles/view/64115
或： http://dx.doi.org/10.1172/JCI64115