Regulation of CAR T cell metabolism

Cover for Immunity
February 16, 2016
Volume 44, Issue 2

View the cover and the story 
on Immunity website

Immunity2016

Recently cancer immunotherapy has become a potential game-changer for treating many types of cancer. Among different immunotherapy strategies, one of the promising one is the adoptive T cell therapy using infusion of genetically redirected autologous T cells – the chimeric antigen receptor (CAR) T cells. We explored the effect of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human therapeutic CAR T cells. The regulation of metabolism in T cells is critical for the control of their expansion, exhaustion and memory formation. We discovered that 4-1BB in the CAR architecture promoted the formation of CD8+ central memory T cells. Biochemical assays and mass spectrometry (MS) analysis revealed that cells with 4-1BB domain developed significantly elevated respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CD28 domains in the CAR architecture led to outgrowth of effector memory cells. These cells showed enhanced glycolytic metabolism. Our study has provided mechanistic insights into the regulation of CAR-T cell fates by different signaling domains through metabolism. Importantly, it also provided potential means for designing engineered T cells towards different fates for therapeutic purposes. This was a collaborative project between Dr. Blair, Dr. Milone and Dr. June.



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