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TNF signaling drives myeloid-derived suppressor cell accumulation
Xueqiang Zhao, … , Joachim Sieper, Zhihai Qin
Xueqiang Zhao, … , Joachim Sieper, Zhihai Qin
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):4094-4104. https://doi.org/10.1172/JCI64115.
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Research Article Oncology

TNF signaling drives myeloid-derived suppressor cell accumulation

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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.

Authors

Xueqiang Zhao, Lijie Rong, Xiaopu Zhao, Xiao Li, Xiaoman Liu, Jingjing Deng, Hao Wu, Xia Xu, Ulrike Erben, Peihua Wu, Uta Syrbe, Joachim Sieper, Zhihai Qin

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Figure 1

Transplanted tumors are spontaneously rejected in Tnfr–/– mice.

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Transplanted tumors are spontaneously rejected in Tnfr–/– mice.
 
Tnfr+/...
Tnfr+/+ (n = 4–5) and Tnfr–/– (n = 7) mice were subcutaneously injected with (A) 5 × 106 J558L cells, (B) 1 × 106 FB61 cells, or (C) 1 × 106 FD99 cells. Tumor volumes after tumor cell inoculation are shown; each line represents the growth curve of a tumor in a single mouse. Similar results were obtained from 2 other independent experiments.
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