Autocrine IL6-mediated activation of the STAT3-DNMT axis silences the TNFa-RIP1 necroptosis pathway to sustain survival and accumulation of myeloid-derived suppressor cells

Alyssa D. Smith, Chunwan Lu, Daniela Payne, Amy V. Paschall, John D. Klement, Priscilla S. Redd, Mohammed L. Ibrahim, Dafeng Yang, Qimei Han, Zhuoqi Liu, Huidong Shi, Thomas J. Hartney, Asha Nayak-Kapoor, Kebin Liu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Although accumulation of myeloid-derived suppressor cells (MDSC) is a hallmark of cancer, the underlying mechanism of this accumulation within the tumor microenvironment remains incompletely understood. We report here that TNFa-RIP1-mediated necroptosis regulates accumulation of MDSCs. In tumor-bearing mice, pharmacologic inhibition of DNMT with the DNA methyl-transferease inhibitor decitabine (DAC) decreased MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes. DAC-induced decreases in MDSC accumulation correlated with increased expression of the myeloid cell lineage-specific transcription factor IRF8 in MDSCs. However, DAC also suppressed MDSC-like cell accumulation in IRF8-deficient mice, indicating that DNA methylation may regulate MDSC survival through an IRF8-independent mechanism. Instead, DAC decreased MDSC accumulation by increasing cell death via disrupting DNA methylation of RIP1-dependent targets of necroptosis. Genome-wide DNA bisulfite sequencing revealed that the Tnf promoter was hypermethylated in tumor-induced MDSCs in vivo. DAC treatment dramatically increased TNFa levels in MDSC in vitro, and neutralizing TNFa significantly increased MDSC accumulation and tumor growth in tumor-bearing mice in vivo. Recombinant TNFa induced MDSC cell death in a dose- and RIP1-dependent manner. IL6 was abundantly expressed in MDSCs in tumor-bearing mice and patients with human colorectal cancer. In vitro, IL6 treatment of MDSC-like cells activated STAT3, increased expression of DNMT1 and DNMT3b, and enhanced survival. Overall, our findings reveal that MDSCs establish a STAT3-DNMT epigenetic axis, regulated by autocrine IL6, to silence TNFa expression. This results in decreased TNFa-induced and RIP1-dependent necroptosis to sustain survival and accumulation.

Original languageEnglish (US)
Pages (from-to)3145-3156
Number of pages12
JournalCancer Research
Volume80
Issue number15
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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