近日，美国斯坦福大学Crystal L. Mackall及其小组发现，肌苷诱导CAR-T细胞的干性特征并增强其效力。该项研究成果于2024年1月25日在线发表在《癌细胞》杂志上。

研究人员试图通过敲除CD39、CD73或腺苷受体2a（A2aR）来增强CAR-T细胞的效力，但观察到的效果并不明显。相反，过表达能将腺苷（Ado）代谢为肌苷（INO）的Ado脱氨酶（ADA-OE）能诱导干性并增强CAR-T的功能。同样，CAR-T细胞暴露于INO可增强功能并诱导干性特征。INO诱导了深刻的新陈代谢重编程，减少了糖酵解，增加了线粒体和糖酵解能力、谷氨酰胺酵解和多胺合成，并对表观基因组进行了重编程，使其具有更强的干性。

使用INO进行的临床规模生产产生了符合临床剂量标准的增效CAR-T细胞产品。这些结果表明，INO是CAR-T细胞新陈代谢和表观遗传干性编程的强效调节剂，为细胞制造提供了一个增强效力的平台。

据了解，Ado介导肿瘤微环境中的免疫抑制，而衰竭的CD8⁺ CAR-T细胞表达CD39和CD73，它们介导Ado生成的近端步骤。

附：英文原文

Title: Inosine induces stemness features in CAR-T cells and enhances potency

Author: Dorota D. Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A. Freitas, Yiyun Chen, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Vimal Keerthi, Amaury Leruste, Malek Bashti, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A. Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L. Davis, Ansuman T. Satpathy, Steven A. Feldman, Elena Sotillo, Crystal L. Mackall

Issue&Volume: 2024-01-25

Abstract: Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.

DOI: 10.1016/j.ccell.2024.01.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00008-4