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记忆细胞的影响

技术资料下载地址: http://www.ncbi.nlm.nih.gov/pubmed/26885860
文献来源: Immunity.
Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

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.

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记忆细胞的影响
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。

文献分享自爱康得生物技术