TNF signaling drives myeloid-derived suppressor cell accumulation.
Zhao, Xueqiang 1,2; Rong, Lijie 1,2; Zhao, Xiaopu 1,2; Li, Xiao 1; Liu, Xiaoman 1; Deng, Jingjing 1,2; Wu, Hao 1; Xu, Xia 1; Erben, Ulrike 3; Wu, Peihua 3; Syrbe, Uta 3; Sieper, Joachim 3; Qin, Zhihai 1
[Article]
Journal of Clinical Investigation.
122(11):4094-4104, November 1, 2012.
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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.
Copyright (C) 2012 The American Society for Clinical Investigation, Inc.
