PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity

Leng Han, Lulu Bai, Chunjing Qu, Enyong Dai, Jiao Liu, Rui Kang, Di Zhou, Daolin Tang, Yanan Zhao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Dendritic cells (DCs) are antigen-presenting cells of the immune system, which play a key role in antitumor immunity by activating cytotoxic T cells. Here, we report that elevated ferroptosis, a lipid peroxidation-mediated cell death, impairs the maturation of DCs and their function in tumor suppression. Ferroptosis is selectively induced in DCs by the GXP4 inhibitor RSL3, but not the SLC7A11 inhibitor erastin. Ferroptotic DCs lose their ability to secrete pro-inflammatory cytokines (TNF and IL6) and express MHC class I in response to the maturation signal of lipopolysaccharide. Moreover, ferroptotic DCs fail to induce CD8+ T cells to produce IFNG/IFNγ. Mechanistically, PPARG/PPARγ, a nuclear receptor involved in the regulation of lipid metabolism, is responsible for RSL3-induced ferroptosis in DCs. Consequently, the genetic depletion of PPARG restores the maturation and function of DCs. Using immunogenic cell death-based DC vaccine models, we further demonstrate that PPARG-mediated ferroptosis of DCs limits antitumor immunity in mice. Together, these findings demonstrate a novel role of ferroptotic DCs in driving an immunosuppressive tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)33-39
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume576
DOIs
StatePublished - Oct 22 2021

Keywords

  • Cytokine
  • Dendritic cells
  • Ferroptosis
  • Immunosuppression
  • Lipid peroxidation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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