Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Cell. 2020 Dec 23;183(7):1848-1866.e26. doi: 10.1016/j.cell.2020.11.009. Epub 2020 Dec 9.
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.
肥胖是一个主要的癌症风险因素，但系统代谢的差异如何改变肿瘤微环境（TME）并影响抗肿瘤免疫尚不清楚。在这里，我们证明高脂肪饮食（HFD）诱导的肥胖会损害小鼠 TME 中的 CD8 T 细胞功能，从而加速肿瘤生长。我们生成了 TME 中细胞代谢的单细胞分辨率图谱，详细说明了它如何随饮食诱导的肥胖而变化。我们发现肿瘤和 CD8 T 细胞对肥胖有不同的代谢适应。肿瘤细胞在 HFD 下增加脂肪摄取，而肿瘤浸润的 CD8 T 细胞则不会。这些差异适应导致 HFD 肿瘤中脂肪酸分配的改变，从而损害 CD8 T 细胞的浸润和功能。在肥胖小鼠中阻断肿瘤细胞的代谢重编程可改善抗肿瘤免疫。对人类癌症的分析显示 CD8 T 细胞标志物存在相似的转录变化，这表明利用代谢来改善癌症免疫疗法的干预措施。
