PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity

• Published in: Biochemical and biophysical research communications 2021-10, Vol.576, p.33-39
• Main Authors: Han, Leng, Bai, Lulu, Qu, Chunjing, Dai, Enyong, Liu, Jiao, Kang, Rui, Zhou, Di, Tang, Daolin, Zhao, Yanan
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cytokine; Dendritic cells; Dendritic Cells - immunology; Disease Models, Animal; Female; Ferroptosis; Ferroptosis - immunology; Immunosuppression; Immunotherapy - methods; Lipid peroxidation; Lipid Peroxidation - immunology; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; PPAR gamma - genetics; PPAR gamma - immunology; PPAR gamma - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.08.082

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. •Selective induction of ferroptosis in DCs.•Ferroptosis impairs DC maturation and function.•PPARG drives ferroptosis in DCs.•Ferroptotic DCs exhibit impaired antitumor activities in mice.