[PDF][PDF] Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells

OU Kawalekar, RS O'Connor, JA Fraietta, L Guo… - Immunity, 2016 - cell.com
OU Kawalekar, RS O'Connor, JA Fraietta, L Guo, SE McGettigan, AD Posey, PR Patel…
Immunity, 2016cell.com
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 …
Summary
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.
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