PROTAC 工程化蛋白/DNA 纳米抗原是癌症免疫治疗中树突状细胞疫苗的有效增强剂
PROTAC-Engineered Protein/DNA Nanoantigen is a Potent Booster for Dendritic Cell Vaccines in Cancer Immunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
PPARG 介导的树突状细胞铁死亡限制抗肿瘤免疫
英文原题：PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity.
查看英文原题
PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity.
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中文摘要
树突状细胞（DCs）是免疫系统的抗原呈递细胞，通过激活细胞毒性T细胞在抗肿瘤免疫中发挥关键作用。在此，我们报道铁死亡（一种脂质过氧化介导的细胞死亡）水平升高会损害DCs的成熟及其肿瘤抑制功能。铁死亡由GPX4抑制剂RSL3选择性诱导于DCs中，而非SLC7A11抑制剂erastin。发生铁死亡的DCs丧失分泌促炎细胞因子（TNF和IL6）的能力，并且无法响应脂多糖的成熟信号表达MHC I类分子。
此外，发生铁死亡的DCs无法诱导CD8+ T细胞产生IFNG/IFNγ。在机制上，PPARG/PPARγ——一种参与脂质代谢调控的核受体——是RSL3诱导DCs铁死亡的原因。
因此，PPARG的基因敲除可恢复DCs的成熟和功能。利用基于免疫原性细胞死亡的DC疫苗模型，我们进一步证明PPARG介导的DCs铁死亡限制了小鼠的抗肿瘤免疫。
总之，这些发现揭示了铁死亡DCs在驱动免疫抑制性肿瘤微环境中的新作用。
展开英文摘要原文
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.
论文信息
- 作者
- Han L、Bai L、Qu C、Dai E、Liu J、Kang R、Zhou D、Tang D
- 第一作者单位
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.China
- 通讯作者单位
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China. Electronic address: zhaoyanan1986@jlu.edu.cn.China
- 期刊
- Biochemical and biophysical research communications2021 Oct 22
- 原文标识
- PubMed 34478917 · DOI 10.1016/j.bbrc.2021.08.082