Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model

Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Natural killer (NK) cell-mediated immunity is crucial for tumor surveillance and therapy. Characterization of the regulatory mechanisms of NK cell function is important for developing novel immunotherapies against HCC. In this study, we used a chemical-induced mouse HCC model to identify the upregulation of Sirtuin2 (SIRT2) in liver NK cells. In particular, SIRT2 was predominantly expressed in liver CD94(+) NK cells. The HCC liver microenvironment induced SIRT2 expression in NK cells. In addition, overexpression of exogenous SIRT2 significantly upregulated the production of cytokines and cytotoxic mediators in activated NK cells. Consistently, SIRT2-overexpressing NK cells showed a stronger tumoricidal effect on hepatoma cells. Moreover, SIRT2 remarkably promoted the phosphorylation of Extracellular-signal-regulated kinase 1/2 (Erk1/2) and p38 Mitogen-activated protein kinases (MAPK) in activated NK cells. SIRT2 knockdown in liver CD94(+) NK cells impaired their cytotoxic effect on hepatoma cells. Our study indicates that SIRT2 enhances the tumoricidal activity of liver NK cells in HCC.