Cell:肥胖如何抑制抗肿瘤免疫?
创作:szx 审核:szx 2020年12月21日
  • 高脂饮食减少瘤内的CD8+ T细胞数量并抑制其功能,加速小鼠肿瘤生长;
  • 高脂饮食诱导肿瘤细胞下调PHD3的表达以增加肿瘤细胞的脂肪摄取,但不影响肿瘤浸润CD8+ T细胞的PHD3表达及脂肪摄取,并改变了CD8+ T细胞在肿瘤内的代谢生态位;
  • 过表达PHD3以阻断高脂饮食诱导的肿瘤细胞代谢重编程,增强小鼠CD8+ T细胞的抗肿瘤免疫应答;
  • 结肠癌患者的肿瘤PHD3表达低于正常组织,肥胖结肠癌患者的PHD3表达低于非肥胖患者,冷肿瘤中的PHD3表达降低。
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szx
肥胖是癌症风险因素之一,但系统性代谢变化如何改变肿瘤微环境并影响抗肿瘤免疫应答尚未明确。Cell上发表的一项最新研究,发现在高脂饮食诱导的肥胖小鼠中,肿瘤浸润CD8+ T细胞的数量减少且功能受到抑制,从而促进肿瘤生长。机制上,高脂饮食诱导肿瘤细胞下调脯氨酰羟化酶(PHD3,可通过抑制长链脂肪酸进入线粒体来调节脂肪酸氧化)的表达,从而增强肿瘤细胞的脂肪摄取,但CD8+ T细胞的PHD3表达及脂肪摄取未受影响。进一步研究发现,恢复肿瘤细胞的PHD3表达可通过增强CD8+ T细胞的功能,以抑制小鼠的肿瘤生长。该研究结果提示,PHD3或可作为调控肿瘤细胞代谢的靶点,增强机体的抗肿瘤免疫应答。
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Cell [IF:38.637]

Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity

肥胖塑造肿瘤微环境代谢以抑制抗肿瘤免疫

10.1016/j.cell.2020.11.009

2020-12-09, Article

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Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8 + T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8 + T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8 + T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8 + T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8 + T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.

First Authors:
Alison E Ringel,Jefte M Drijvers

Correspondence Authors:
Arlene H Sharpe,Marcia C Haigis

All Authors:
Alison E Ringel,Jefte M Drijvers,Gregory J Baker,Alessia Catozzi,Juan C García-Cañaveras,Brandon M Gassaway,Brian C Miller,Vikram R Juneja,Thao H Nguyen,Shakchhi Joshi,Cong-Hui Yao,Haejin Yoon,Peter T Sage,Martin W LaFleur,Justin D Trombley,Connor A Jacobson,Zoltan Maliga,Steven P Gygi,Peter K Sorger,Joshua D Rabinowitz,Arlene H Sharpe,Marcia C Haigis

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