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PMID: 23064360 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

TNF signaling drives myeloid-derived suppressor cell accumulation.

The Journal of clinical investigation ·Vol. 122 ·No. 11 ·2012-11-00 ·Pages 4094-104

Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J, Wu H, Xu X, Erben U, Wu P, Syrbe U, Sieper J, Qin Z

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.

MeSH Terms
Animals CASP8 and FADD-Like Apoptosis Regulating Protein/biosynthesis,genetics,immunology Caspase 8/genetics,immunology,metabolism Cell Line, Tumor Graft Rejection/genetics,immunology,metabolism,pathology Mice Mice, Inbred BALB C Mice, Knockout Myeloid Cells/immunology,metabolism,pathology Neoplasm Transplantation Neoplasms/genetics,immunology,metabolism,pathology Receptors, Tumor Necrosis Factor, Type I/genetics,immunology,metabolism Receptors, Tumor Necrosis Factor, Type II/genetics,immunology,metabolism Signal Transduction/genetics,immunology T-Lymphocytes/immunology,metabolism,pathology Tumor Escape Tumor Necrosis Factor-alpha/genetics,immunology,metabolism
Chemicals
CASP8 and FADD-Like Apoptosis Regulating Protein Cflar protein, mouse Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Tnfrsf1a protein, mouse Tumor Necrosis Factor-alpha Casp8 protein, mouse Caspase 8
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Zhao Xueqiang
Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Rong Lijie
Zhao Xiaopu
Li Xiao
Liu Xiaoman
Deng Jingjing
Wu Hao
Xu Xia
Erben Ulrike
Wu Peihua
Syrbe Uta
Sieper Joachim
Qin Zhihai
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI64115
Published
2012-11-00
Epub
2012-00-15
Pages
4094-104
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3484453
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI64115 PMC Full Text View journal details
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