Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells
Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells
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脂质生物合成受损阻碍瘤内 iNKT 细胞的抗肿瘤功效
DOI：
10.1038/s41467-020-14332-x
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发表时间：
2020-01-23
影响因子：
16.6
通讯作者：
Bai, Li
中科院分区：
文献类型：
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作者：
Fu, Sicheng;He, Kaixin;Bai, Li
不变自然杀伤T细胞(INKT)在肿瘤微环境中的功能障碍阻碍了其抗肿瘤效应，其潜在机制尚不清楚。在这里，我们报道了iNKT细胞在激活后增加了脂质的生物合成，这是由PPARγ和PLZF通过促进Srebf1的转录而协同促进的。在这些脂质中，胆固醇是iNKT细胞产生最佳干扰素-γ所必需的。肿瘤微环境中的乳酸减少瘤内iNKT细胞PPARγ的表达，从而减少其胆固醇合成和干扰素-γ的产生。重要的是，PPARγ激动剂吡格列酮是一种治疗2型糖尿病的噻唑烷二酮类药物，它成功地恢复了人类患者和小鼠模型肿瘤浸润性iNKT细胞中干扰素-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时间。我们的研究提供了一种策略，通过促进iNKT细胞免疫疗法的脂质生物合成来增强其抗肿瘤效果。
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 ofSrebf1. 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.