Leucine metabolism is a promising new approach to study the interplay between T cells and cancer cells

Abstract Cancer and T cells undergo similar metabolic reprogramming during proliferation to support increased biosynthetic and energy demands. They both rely on high rates of glycolysis while retaining mitochondrial respiration, a phenomenon known as the Warburg effect. In the tumor microenvironment, tumor cells can escape immune surveillance by competing with T cells for common metabolites and redirecting nutrients for their own advantage. To gain insight into the relationship between T cells and cancer cells, we studied the effect of leucine metabolism on T cells and their cancerous counterpart, EL-4 lymphoma cells. Our previous results showed that a loss of expression of leucine degrading enzymes (cytosolic or mitochondrial branched chain aminotransferases, BCATc and BCATm, respectively) increased intracellular leucine concentrations and stimulated glycolytic rate in activated T cells. These results correlated with activation of complex 1 of the mammalian target of rapamycin (mTORC1). Continuation of this study with EL-4 lymphoma cells, grown in leucine free media or treated with the leucine antagonist, n-acetyl-leucine amide, revealed a decrease in glycolysis, glycolytic capacity, and glycolytic reserve while mTORC1 was only moderately impacted. The oxygen consumption rate was stimulated in T cells lacking BCATc and/or BCATm but was decreased in the absence of leucine in EL-4 cells. The results suggest that T cells and their cancerous counterpart use leucine in a similar manner and that leucine is essential for the regulation of glucose and oxygen metabolism in either cell type. Future studies targeting leucine metabolism in the tumor microenvironment will aim to improve the effectiveness of T cells to fight cancer cells.