CAR-T细胞中不同信号的辅助受体调节特异性代谢途径及其对... - 中国病毒学论坛|我们一直在坚持！

Chimeric antigen receptors (CARs)redirect T cell cytotoxicity against cancer cells, providing a promisingapproach to cancer immunotherapy. Despite extensive clinical use, theattributes of CAR co-stimulatory domains that impact persistence and resistanceto exhaustion of CAR-T cells remain largelyundefined. Here, we report the influence of signaling domains of coreceptorsCD28 and 4-1BB on the metaboliccharacteristics of human CAR T cells. Inclusion of 4-1BB in the CARarchitecture promoted the outgrowth of CD8+ central memory T cells thathad significantly enhanced respiratory capacity, increased fatty acid oxidationand enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yieldedeffector memory cells with a genetic signature consistent with enhancedglycolysis. These results provide, at least in part, a mechanistic insight intothe differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains inclinical trials and inform the design of future CAR T cell therapies.

CARs介导T细胞对癌症细胞的毒性，提供了一种有前途的免疫治疗癌症的途径。尽管进行了大量的临床应用，影响CAR-T细胞耐久性和抗衰亡能力的CAR的共刺激域的属性仍然有很多不明了的地方。在本文中，我们报道了信号受体CD28和4-1BB域对人CAR-T细胞的代谢特征的影响。包含4-1BB的CAR结构能够增加CD8阳性记忆T细胞的增殖，这能够明显增加呼吸能力，增加脂肪酸氧化，增强线粒体生物合成。这些结果说明，至少部分的给出了一个对于表达4-1BB和CD28信号域的CAR-T细胞在耐久性上的差别，并且给出了将来对于CAR-T细胞治疗的设计。