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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TNF signaling drives myeloid-derived suppressor cell accumulation

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 4

Enhanced caspase-8 activity is responsible for the impaired accumulation of CD11b+Gr1+ cells in Tnfr–/– mice.

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Enhanced caspase-8 activity is responsible for the impaired accumulation...
(A) Tnfr+/+ and Tnfr–/– mice were intraperitoneally injected with 1 mg BrdU 3, 5, and 8 days after FB61 inoculation. After an additional 24 hours, CD11b+Gr1+ cells in total bone marrow cells were gated (left), and BrdU incorporation was determined (right). Numbers indicate percent BrdU+ cells in gated cells. n = 5 per group. (B) Spleen cells were prepared 8–10 days after FB61 cell inoculation and stained for CD11b, Gr1, and annexin V. Numbers denote percent annexin V+ cells in gated CD11b+Gr1+ cells. (C) Proportion of annexin V+CD11b+Gr1+ cells, expressed as percent of total CD11b+Gr1+ cells (mean ± SEM). n = 3 per group. **P < 0.01. (D) Splenic CD11b+Gr1+ cells from tumor-bearing Tnfr+/+ and Tnfr–/– mice were lysed, and caspase-8 activities were determined by colorimetric activity assay (mean ± SEM). n = 3–5 per group. **P < 0.01. (E) Total cell lysates were subjected to cleaved caspase-8–specific Western blot. β-actin served as internal control. (F) MDSCs were in vitro induced from Tnfr+/+ and Tnfr–/– bone marrow cells. 6 hours later, z-VAD, z-IETD, or DMSO (as control) was added to the medium. Data (mean ± SEM) denote percent CD11b+Gr1+ cells in total living cells in the culture. *P < 0.05.