L-Arginine Regulates T-cell Metabolism to Promote Antitumor Activity

T-cell survival and antitumor activity are dependent on metabolic fitness, and activated T cells adapt their metabolism to use large amounts of glucose, amino acids, and fatty acids. To characterize metabolic adaptations underlying T-cell activation, Geiger and colleagues used high-resolution mass spectrometry to analyze the proteome and metabolome of human primary naïve T cells. A total of 2,824 differentially expressed proteins were identified in activated T cells compared with nonactivated T cells, and upregulated proteins included enzymes involved in several metabolic pathways including arginine metabolism. Of 429 identified metabolites, 49 were increased upon T-cell activation and only 14 were decreased, including three members of the same metabolic pathway: arginine, ornithine, and N-acetylornithine. T-cell activation resulted in a rapid decrease in intracellular arginine despite enhanced L-arginine uptake due to the rapid conversion of L-arginine into downstream metabolites, mainly by the mitochondrial enzyme arginase 2 (ARG2), which was upregulated in activated T cells. T cells activated in L-arginine–supplemented medium consumed less glucose and exhibited reduced expression of glucose transporters and glycolytic enzymes, altogether indicating that L-arginine reduced glycolytic flux. Conversely, oxidative phosphorylation was enhanced by increased intracellular L-arginine in activated T cells. In addition to the metabolic affects, L-arginine influenced the fate of activated T cells; elevated L-arginine levels limited T-cell differentiation and promoted the maintenance of central-memory T-cell characteristics. Further, L-arginine increased the survival of activated CD4⁺ and CD8⁺ T cells. In vivo, supplementation with L-arginine enhanced activated T-cell survival, and adoptive transfer of L-arginine–treated cells activated by tumor antigen resulted in an enhanced antitumor response in melanoma xenografts. Together, these findings indicate that L-arginine promotes T-cell survival and antitumor activity and suggest that L-arginine may have the potential to enhance T-cell therapies.

Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167:829–42.e13.

• ©2016 American Association for Cancer Research.