TNF signaling drives myeloid-derived suppressor cell accumulation
Xueqiang Zhao1, Lijie Rong, Xiaopu Zhao
1Key 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.
The Journal of Clinical Investigation
|October 16, 2012
Summary
Tumor necrosis factor (TNF) signaling drives myeloid-derived suppressor cells (MDSCs) accumulation, promoting tumor growth. Blocking TNF receptors impairs MDSC expansion, offering a potential cancer immunotherapy strategy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Mechanisms
Background:
- Tumor necrosis factor (TNF) is an inflammatory cytokine found in the tumor microenvironment.
- TNF promotes tumor growth and hinders anti-cancer immune responses.
- TNF receptor-deficient mice exhibit spontaneous tumor rejection, but underlying mechanisms are unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms by which TNF signaling influences tumor rejection.
- To investigate the role of TNF in the accumulation of myeloid-derived suppressor cells (MDSCs).
Main Methods:
- Utilized TNF receptor-deficient (Tnfr-/-) mice models.
- Analyzed the peripheral accumulation and bone marrow induction of MDSCs.
- Investigated the role of TNFR-1 and TNFR-2 signaling pathways.
- Assessed the impact of c-FLIP and caspase-8 activity.
- Examined the effects of caspase inhibitors on MDSC induction.
Main Results:
- TNF signaling drives the peripheral accumulation of MDSCs.
- MDSC accumulation was significantly impaired in Tnfr-/- mice.
- TNFR-2 signaling, not TNFR-1, promoted MDSC survival via c-FLIP upregulation and caspase-8 inhibition.
- Loss of TNFRs reduced MDSC induction from bone marrow cells.
- Caspase inhibitors reversed the impaired MDSC induction in TNFR-deficient settings.
Conclusions:
- TNF receptor signaling, particularly TNFR-2, is crucial for MDSC survival and accumulation.
- MDSC expansion mediated by TNF signaling contributes to immune evasion in tumors.
- Targeting TNFR-2 signaling may represent a novel therapeutic strategy to enhance anti-tumor immunity.
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