Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells

作者：Kawalekar, Omkar U.; O'Connor, Roddy S.; Fraietta, Joseph A.; Guo, Lili; McGettigan, Shannon E.; Posey, Avery D., Jr.; Patel, Prachi R.; Guedan, Sonia; Scholler, John; Keith, Brian; Snyder, Nathaniel; Blair, Ian; Milone, Michael C.; June, Carl H.^*

来源：Immunity, 2016, 44(2): 380-390.

DOI：10.1016/j.immuni.2016.01.021

• SPARE RESPIRATORY CAPACITY
• CHIMERIC ANTIGEN RECEPTORS
• MITOCHONDRIAL COMPLEX-I
• ADOPTIVE IMMUNOTHERAPY
• SUSTAINED REMISSIONS
• ANTITUMOR-ACTIVITY
• OXIDATIVE STRESS
• ACTIVATION
• IMMUNOGLOBULIN
• COSTIMULATION

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.

• 出版日期2016-2-16