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Targeting Sirt2 reprograms T cell metabolism for effective immune response

ABSTRACT: There is a growing evidence that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However the mechanisms underlying the metabolic switch in T cells remain unclear. Here we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cells activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated similar phenotype. Taken together our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Spleen

SUBMITTER: John Koomen

PROVIDER: ST001373 | MetabolomicsWorkbench | Wed Jul 24 00:00:00 BST 2019

REPOSITORIES: MetabolomicsWorkbench

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