TNF signaling drives myeloid-derived suppressor cell accumulation

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 mechanism...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation Vol. 122; no. 11; pp. 4094 - 4104
Main Authors: Zhao, Xueqiang, Rong, Lijie, Zhao, Xiaopu, Li, Xiao, Liu, Xiaoman, Deng, Jingjing, Wu, Hao, Xu, Xia, Erben, Ulrike, Wu, Peihua, Syrbe, Uta, Sieper, Joachim, Qin, Zhihai
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.11.2012
Subjects:
Animals
Apoptosis
Biomedical research
Cancer
CASP8 and FADD-Like Apoptosis Regulating Protein - biosynthesis
CASP8 and FADD-Like Apoptosis Regulating Protein - genetics
CASP8 and FADD-Like Apoptosis Regulating Protein - immunology
Caspase 8 - genetics
Caspase 8 - immunology
Caspase 8 - metabolism
Cell Line, Tumor
Cellular signal transduction
Cytotoxicity
Dendritic cells
Gene expression
Genetic aspects
Graft Rejection - genetics
Graft Rejection - immunology
Graft Rejection - metabolism
Graft Rejection - pathology
Inflammation
Mice
Mice, Inbred BALB C
Mice, Knockout
Myeloid Cells - immunology
Myeloid Cells - metabolism
Myeloid Cells - pathology
Neoplasm Transplantation
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - metabolism
Neoplasms - pathology
Properties
Receptors, Tumor Necrosis Factor, Type I - genetics
Receptors, Tumor Necrosis Factor, Type I - immunology
Receptors, Tumor Necrosis Factor, Type I - metabolism
Receptors, Tumor Necrosis Factor, Type II - genetics
Receptors, Tumor Necrosis Factor, Type II - immunology
Receptors, Tumor Necrosis Factor, Type II - metabolism
Signal Transduction - genetics
Signal Transduction - immunology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
T-Lymphocytes - pathology
Tumor Escape
Tumor necrosis factor
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - immunology
Tumor Necrosis Factor-alpha - metabolism
Tumors
China
ISSN:0021-9738, 1558-8238, 1558-8238
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 14
ObjectType-Article-1
ObjectType-Feature-2
content type line 23
Authorship note: Xueqiang Zhao, Lijie Rong, and Xiaopu Zhao contributed equally to this work.
ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI64115