Sirt2 inhibition reprograms T cell metabolism for optimal anti-tumor immunity: Lysine Acetylation

ABSTRACT: Growing evidence indicates 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 cell 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 a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell

DISEASE(S): Melanoma

SUBMITTER: John Koomen  

LAB HEAD: Sungjune Kim, MD

PROVIDER: PXD012796 | Pride | 2020-06-15

REPOSITORIES: Pride