提高 CAR-T 疗效新策略，《细胞》子刊：调节这一代谢通路有作用
专业点燃希望约 5 分钟首先，CD39是CAR-T细胞功能减弱的标志。大量耗竭的CD39+ CAR-T细胞共表达CD73，产生腺苷(Ado)并通过A2aR介导免疫抑制。而腺苷脱氨酶(ADA)可将腺苷(Ado)分解为肌苷（INO），从而减少Ado介导的免疫抑制。为此，研究设置了ADA过表达的实验组(ADA-OE)。针对转录组学和表型特征的研究发现，腺苷脱氨酶的过表达(ADA-OE)增加了CAR-T细胞的干性特征，降低了终末分化。
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排版 | Sheila 校对 | uu
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原文摘要（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