Autocrine IL6 activates the STAT3-DNMT axis to silence the TNFa-RIP1 necroptosis pathway to sustain myeloid-derived suppressor cell survival and accumulation

ABSTRACT: Massive accumulation of myeloid-derived suppressor cells (MDSCs) is a hallmark of cancer. It is well-known that proinflammatory mediators induce MDSC accumulation. However, the functions of cell death pathways in MDSC survival and the mechanism underlying regulation of cell death pathways in MDSCs are still elusive. Herein, we determined that DNA methylation sustains MDSC accumulation in tumor-bearing mice since pharmacological inhibition of DNMTs with Dacitabine abolished MDSC accumulation and activated antigen-specific cytotoxic T lymphocytes in tumor-bearing mice. Decreased MDSC accumulation is correlated with increased IRF8 expression in MDSCs. However, Dacitabine also abolished CD11b+Gr1+ MDSC-like cell accumulation in IRF8 KO mice, suggesting that DNA methylation regulates MDSC accumulation at the post lineage differentiation stage. Use of cell death pathway-selective inhibitors identified necroptosis as the target of DNA methylation in MDSCs. Genome-wide DNA bisulfite sequencing revealed that the promoter of Tnf is hypermethylated in tumor-induced MDSCs. Consequently, decitabine dramatically increased TNF level in MDSCs and neutralizing TNF significantly decreased Dacitabine-induced MDSC cell death. Recombinant TNF induced MDSC cell cells in a dose and RIP1-dependent manner. Inhibition of RIP1 or RIP3 did not decrease TNF expression in MDSCs. Our data determined that the TNF-RIP1 necroptosis pathway is responsible at least in part for MDSC accumulation and that the IL6-activated DNMTs hypermethylate Tnf to impair necroptosis pathway to maintain MDSC accumulation in cancer. Our data depict the IL6-STAT3-DNMT-TNFa-RIP1 necroptosis pathway as a molecular target for suppressing MDSC accumulation in cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE144649 | GEO | 2020/08/01

REPOSITORIES: GEO