Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
Cell Metab. 2021 Dec 7;33(12):2415-2427.e6. doi: 10.1016/j.cmet.2021.11.010.
Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8 T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8 Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity.
代谢编程与 T 细胞的抗肿瘤特性密切相关。为了研究与增强抗肿瘤 T 细胞功能相关的代谢途径，我们利用代谢组学方法来描述在小鼠模型中具有不同抗肿瘤活性的三种不同的 CD8 T 细胞亚群，其中 IL-22 产生的 Tc22 细胞表现出最强大的抗肿瘤活性。Tc22 细胞表现出泛酸/辅酶 A（CoA）途径的上调和分化所需的氧化磷酸化（OXPHOS）。外源性 CoA 的给药将 T 细胞重新编程为增加 OXPHOS，并通过转录因子 HIF-1α 和芳基烃受体（AhR）独立于极化条件采用 CD8 Tc22 表型。在小鼠肿瘤模型中，用 CoA 前体泛酸处理小鼠增强了抗 PD-L1 抗体治疗的疗效。在黑色素瘤患者中，治疗前血浆泛酸水平与对抗 PD1 治疗的反应呈正相关。总的来说，我们的数据表明泛酸及其代谢物 CoA 驱动 T 细胞极化、生物能量和抗肿瘤免疫。
