Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer.
Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer.
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DOI：
10.1158/0008-5472.can-17-2460
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发表时间：
2018-04-01
期刊：
影响因子：
11.2
通讯作者：
Zhang Y
中科院分区：
文献类型：
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作者：
Li L;Wang L;Li J;Fan Z;Yang L;Zhang Z;Zhang C;Yue D;Qin G;Zhang T;Li F;Chen X;Ping Y;Wang D;Gao Q;He Q;Huang L;Li H;Huang J;Zhao X;Xue W;Sun Z;Lu J;Yu JJ;Zhao J;Zhang B;Zhang Y
二甲双胍是一种治疗2型糖尿病的广泛处方药物，具有抗肿瘤活性，但其作用机制尚不清楚。我们在这里表明，二甲双胍治疗通过下调单核和多核MDSC亚群上CD39和CD73的表达和胞外酶活性来阻断卵巢癌(OC)患者的髓源性抑制细胞(MDSC)的抑制功能。二甲双胍可激活AMP激活的蛋白激酶α(AMPKα)，进而抑制低氧诱导因子α(HIF-1α)的表达，而HIF-1是诱导CD39/CD73表达的关键。此外，二甲双胍治疗与合并OC的糖尿病患者的总生存期延长有关，同时伴有循环CD39+CD73+MDSC频率的降低和循环CD8+T细胞抗肿瘤活性的增加。我们的结果强调了二甲双胍对MDSC的直接作用，并提示二甲双胍可能通过抑制卵巢癌患者CD39/CD73依赖的MDSC免疫抑制而改善抗肿瘤T细胞免疫，从而产生临床益处。
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 (OC) 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 α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with OC, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+MDSC and a concomitant increase in the antitumor activities of circulating CD8+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-dependent MDSC immunosuppression in OC patients.