BioProject

Metabolism is a key driver of T cell functions, and the switch from oxidative-phosphorylation to aerobic glycolysis is a hallmark of T cell activation. More...

Metabolism is a key driver of T cell functions, and the switch from oxidative-phosphorylation to aerobic glycolysis is a hallmark of T cell activation. However, the mechanisms underlying the metabolic switch remain unclear. Here, we report that the Sirtuin-2 (Sirt2) deacetylase protein functions as a metabolic checkpoint that harnesses T cell effector functions and impairs anti-tumor immunity. Specifically, upregulation of Sirt2 expression in human tumor-infiltrating T lymphocytes (TILs) negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer. Mechanistically, Sirt2 suppresses aerobic glycolysis by deacetylating key glycolytic enzymes. Accordingly, Sirt2-deficient T cells manifest increased glycolysis, display enhanced proliferation and effector functions, and have superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and enhanced effector functions. These findings indicate Sirt2 as an actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies. Overall design: Spleens were collected from C57BL/6J and Sirt2-/- mice and were processed into single-cell suspensions. CD4+ T cells were negatively enriched and were either followed directly by RNA extraction (naïve = 0 hour) or stimulated for 24 hours. WT and Sirt2-/- CD4+ T cells were activated with plate-bound anti-CD3 antibody (5 μg/ml, 145-2C11, BioXCell) for 24 hours. Less...