Effects of fumarate on the metabolic reprogramming of aging T-cells associated with rescue of the T-cell anti-tumor functions
Changes in mitochondrial bioenergetics in aging T-cells play a key role in the decrease in T-cell function and tumor resistance with aging. The bioactive sphingolipid ceramide, induced by aging stress, is a major player in these changes, as its accumulation at the mitochondrial membranes of both mouse and human aging T-cells induces ceramide-dependent mitophagy, which decreases T-cell viability, cytokine secretion, and anti-tumor activity. Besides lipid signaling, our findings show a general depletion of tricarboxylic acid cycle (TCA) metabolites in aging T-cells, with pools of fumarate, malate, and argininosuccinate significantly decreasing in both mouse and human aging T-cells. In vivo supplementation of fumarate to mouse T-cells seemed to correct some of the functional defects observed in aging, with a protection of T-cell viability, cytokine production, and tumor killing capacity in co-cultures with tumor cells. The fumarate supplementation also led to a decrease in ceramide-dependent mitophagy in the aging T-cells, indicating an interplay between ceramide-dependent mitophagy and fumarate metabolism. Here, the RNAseq data shows a reversal of the genetic signature of aging in T-cells upon supplying fumarate, associated with a significant increase in different metabolic enzymes. Overall design: 24-month old C57BL/6 mice were treated with 10mg/kg fumarate for 2 months. After two months of treatment, T-cells were collected from mice treated with fumarate or vehicle, as well as young 2 month old mice. T-cells were then activated in vitro with plate-bound CD3 (2ug/ml) and CD28 (5ug/ml) in the presence of IL-2 (100IU/ml). T-cells were then collected and RNA was extracted for RNAseq.