Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells
Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells
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DOI：
10.1016/j.immuni.2016.01.021
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发表时间：
2016-02-16
期刊：
影响因子：
32.4
通讯作者：
June, Carl H.
中科院分区：
文献类型：
--
作者：
Kawalekar, Omkar U.;O'Connor, Roddy S.;June, Carl H.
嵌合抗原受体（汽车）重定向T细胞对癌细胞的细胞毒性，为癌症免疫治疗提供了一种有前途的方法。尽管广泛的临床应用，影响CAR-T细胞的持久性和对耗尽的抗性的CAR共刺激结构域的属性仍然在很大程度上不确定。在这里，我们报告了辅助受体CD 28和4-1BB的信号结构域对人CAR T细胞代谢特征的影响。在CAR结构中包含4-1BB促进了CD 8（+）中央记忆T细胞的生长，这些细胞具有显著增强的呼吸能力、增加的脂肪酸氧化和增强的线粒体生物合成。相比之下，具有CD 28结构域的CAR T细胞产生具有与增强的糖酵解一致的遗传特征的效应记忆细胞。这些结果至少部分地提供了对临床试验中表达4-1BB或CD 28信号传导结构域的CAR-T细胞的差异持久性的机制见解，并为未来CAR T细胞疗法的设计提供了信息。
Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.