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Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells.

脂质生物合成受损阻碍了瘤内 iNKT 细胞的抗肿瘤疗效。

  • 影响因子:12.19
  • DOI:10.1038/s41467-020-14332-x
  • 作者列表:"Fu S","He K","Tian C","Sun H","Zhu C","Bai S","Liu J","Wu Q","Xie D","Yue T","Shen Z","Dai Q","Yu X","Zhu S","Liu G","Zhou R","Duan S","Tian Z","Xu T","Wang H","Bai L
  • 发表时间:2020-01-23
Abstract

:Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

摘要

: 肿瘤微环境中不变自然杀伤 T (iNKT) 细胞的功能障碍阻碍了其抗肿瘤疗效,其潜在机制仍不清楚。这里我们报道 iNKT 细胞激活后增加脂质生物合成,ppar γ 和 PLZF 通过增强 srebf1 的转录协同促进脂质生物合成。在这些脂质中,胆固醇是 iNKT 细胞产生最佳 IFN-γ 所必需的。肿瘤微环境中的乳酸降低瘤内 iNKT 细胞中 ppar γ 的表达,从而减少其胆固醇合成和 IFN-γ 的产生。重要的是,ppar γ 激动剂吡格列酮,一种治疗 2 型糖尿病的噻唑烷二酮类药物,成功地恢复了人类患者和小鼠模型肿瘤浸润 iNKT 细胞中 IFN-γ 的产生。吡格列酮和 α-半乳糖神经酰胺联合治疗可显著增强 iNKT 细胞介导的抗肿瘤免疫反应,延长荷瘤小鼠的生存期。我们的研究提供了一种策略,通过促进其脂质生物合成来增强基于 iNKT 细胞的免疫疗法的抗肿瘤疗效。

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影响因子:12.19
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