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

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 2

Peripheral accumulation of CD11b+Gr1+ cells is impaired in Tnfr–/– mice.

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Peripheral accumulation of CD11b+Gr1+ cells is impaired in Tnfr–/– mice....
(A) Tnfr+/+ and Tnfr–/– mice were subcutaneously injected with 1 × 106 FB61 cells or PBS as control. 8–10 days after tumor cell inoculation, single splenocytes were stained for CD11b and Gr1 and assessed by flow cytometry. Left: Gated CD11b+Gr1+ cells. Right: Percent CD11b+Gr1+ cells in tumor-bearing Tnfr+/+ and Tnfr–/– mice and corresponding controls. Bars denote means. **P < 0.01. (B) Absolute number of CD11b+Gr1+ cells in spleens of tumor-bearing mice and corresponding controls. Data are mean ± SEM. *P < 0.05. (C and D) Percent CD11b+Gr1+ cells relative to total cells for (C) peripheral blood and (D) tumor tissues. n = 5 per group. Data are mean ± SEM. *P < 0.05. (E) CD11b+ and Gr1+ cells in tumor and spleen sections of Tnfr+/+ and Tnfr–/– mice were visualized by immunofluorescence staining. Nuclei were counterstained with DAPI. Images are representative of at least 3 mice per group. Original magnification, ×200 (tumor); ×100 (spleen). Scale bars: 300 μm. (F) Spleen cells as above were stained for flow cytometry analysis. Unstained Tnfr+/+ splenocytes were used as a control.