(Cell, IF:38.637)Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity

Ringel Alison E,Drijvers Jefte M,Baker Gregory J et al. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.[J] .Cell, 2020, undefined: undefined.

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 obesityimpairs 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.

肥胖是一個主要的癌症危險因素，但系統代謝的差異如何改變腫瘤微環境(TME)並影響抗腫瘤免疫尚不清楚。在這裡，我們證明了高脂飲食(HFD)誘導的肥胖損害了小鼠TME中CD8 T細胞的功能，加速了腫瘤的生長。我們製作了TME細胞代謝的單細胞解析度圖譜，詳細描述了它是如何隨著飲食誘導的肥胖而改變的。我們發現，腫瘤和CD8 T細胞對肥胖表現出明顯的代謝適應。腫瘤細胞透過HFD增加脂肪攝取，而腫瘤浸潤性CD8 T細胞不增加脂肪攝取。這些不同的適應性導致HFD腫瘤中脂肪酸分配的改變，損害CD8 T細胞的浸潤和功能。阻斷肥胖小鼠腫瘤細胞的代謝重程式設計可提高抗腫瘤免疫力。對人類癌症的分析顯示，CD8 T細胞標誌物的轉錄變化類似，這表明可以利用新陳代謝來改善癌症免疫治療。