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 6

TNFR-2 signaling maintains survival of CD11b+Gr1+ cells.

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TNFR-2 signaling maintains survival of CD11b+Gr1+ cells. (A) Tnfr+/+, ...
(A) Tnfr+/+, Tnfr1–/–, Tnfr2–/–, and Tnfr–/– mice were subcutaneously injected with 1 × 106 FB61 cells. Tumor volumes were measured after tumor cell inoculation (mean ± SEM). n = 5–7 per group. *P < 0.05. (B) Spleen cells were prepared 8–10 days after tumor cell inoculation, stained for CD11b and Gr1, and analyzed by flow cytometry. Data (mean ± SEM) represent percent CD11b+Gr1+ cells of total spleen cells. *P < 0.05. (C) Accumulation of CD11b+ and Gr1+ cells in the spleen of tumor-bearing mice, determined by immunofluorescence staining (see Methods). Dotted outlines denote germinal centers. Images are representative of at least 3 mice. Original magnification, ×100 (CD11b); ×200 (Gr1). Scale bars: 300 μm. (D) Total cell lysates were prepared from isolated Tnfr1–/– and Tnfr2–/– CD11b+Gr1+ cells after stimulation with 20 ng/ml TNF for the indicated times. Levels of TRAF2, p–NF-κB p65, p-IκBα, and p-IKKα/β, c-FLIP, and cleaved caspase-8 were determined by Western blot. See Figure 5C for expression levels of respective molecules in Tnfr+/+ mice (controls). β-actin was used as an internal control. Representative images are shown for 3 independent experiments.