加拿大健康网络大学玛格丽特公主癌症中心Pamela S. Ohashi研究组发现辅酶 A (CoA)为 T 细胞抗肿瘤免疫提供燃料。2021年12月7日出版的《细胞—代谢》杂志发表了这项成果。

为了研究与抗肿瘤 T 细胞功能增强相关的代谢途径，他们利用代谢组学方法来表征小鼠模型中具有不同程度抗肿瘤活性的三种不同 CD8+ T 细胞亚群，其中产生 IL-22 的 Tc22 细胞表现出最强的抗肿瘤活性。Tc22s 证明了泛酸/ CoA途径的上调和氧化磷酸化 (OXPHOS) 分化的必要条件。通过转录因子 HIF-1α 和芳烃受体 (AhR)，外源施用 CoA 重编程 T 细胞以增加 OXPHOS 并采用独立于极化条件的 CD8+ Tc22 表型。

在小鼠肿瘤模型中，用 CoA 前体泛酸治疗小鼠可增强抗 PDL1 抗体治疗的功效。在黑色素瘤患者中，治疗前血浆泛酸水平与抗 PD1 治疗反应呈正相关。总的来说，他们的数据表明泛酸及其代谢物 CoA 驱动 T 细胞极化、生物能量学和抗肿瘤免疫。

据悉，代谢编程与 T 细胞的抗肿瘤特性有着错综复杂的联系。

附：英文原文

Title: Coenzyme A fuels T cell anti-tumor immunity

Author: Michael St. Paul, Samuel D. Saibil, SeongJun Han, Kavita Israni-Winger, Scott C. Lien, Rob C. Laister, Azin Sayad, Susanne Penny, Rodabe N. Amaria, Lauren E. Haydu, Carlos R. Garcia-Batres, Meghan Kates, David T. Mulder, Céline Robert-Tissot, Matthew J. Gold, Charles W. Tran, Alisha R. Elford, Linh T. Nguyen, Trevor J. Pugh, Devanand M. Pinto, Jennifer A. Wargo, Pamela S. Ohashi

Issue&Volume: 2021/12/07

Abstract: 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 whichIL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstratedupregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidativephosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammedT cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factorsHIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatmentof mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibodytherapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels werepositively correlated with the response to anti-PD1 therapy. Collectively, our datademonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics,and anti-tumor immunity.

DOI: 10.1016/j.cmet.2021.11.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00538-6