Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase a and subsequently suppressed hypoxia-inducible factor a, which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39 ^þ CD73 ^þ MDSC and a concomitant increase in the antitumor activities of circulating CD8 ^þ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-depen-dent MDSC immunosuppression in ovarian cancer patients. Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells.