Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer
Authors: Zhi Sun
Zhen Zhang
Yu Ping
Jieyao Li
Jane J Yu
Jingli Lu
Qun Gao
Wenhua Xue
Zhirui Fan
Feng Li
Lan Huang
Yi Zhang
Xinfeng Chen
Hong Li
Dan Wang
Guohui Qin
Liping Wang
Xuan Zhao
Qianyi He
Jianmin Huang
Chaoqi Zhang
Dongli Yue
Bin Zhang
Jie Zhao
Li Yang
Lifeng Li
Tengfei Zhang
Journal: Cancer Research (2018)
Discipline: CLINICAL MEDICINE
Keywords: Metformin; myeloid-derived suppressor cells; CD39; CD73; AMP-activated protein kinase α
Affiliations: Biotherapy Center and Cancer Center, First Affiliated Hospital of Zhengzhou University ., First Affiliated Hospital of Zhengzhou University., Oncology, First Affiliated Hospital of Zhengzhou University., Biotherapy Center, First Affiliated Hospital of Zhengzhou University., Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China., Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China., Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati., Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.  ., School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China., Key Laboratory for Tumor Immunology and Biotherapy of Henan Province, Zhengzhou, Henan, China.

Abstract:  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 α and subsequently suppressed hypoxia-inducible factor α, 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+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 ovarian cancer patients.Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells. Cancer Res; 78(7); 1779-91. ©2018 AACR. 

Retracted: No

PubPeer comments:
 Dear Dr. Xu-Feng Huang, Thank you for your attention to our research. In response to your questions, we have carefully checked the manuscript and our original data, as for Q1, in Fig. 2H in order to make the results of flow cytometry more beautiful, researchers sometimes set the gates manually, but the results have not changed. As a gel photo is rotated and re-used in Fig. 3A(Q2), after careful review, we found that the metformin concentration treatment group did not have any problems, but there was an error in the compound C treatment group in Fig. 3A. We apologize for any confusion it may have caused. We have sent the corrigendum materials to the editorial office of Cancer Research for correction. As for Q3, in Fig. 5A, the dots in the flow plots have different sizes and colors because we separately processed and collected more cells in the control group. As for Q4, in Fig. 2A and 2H, the dots areas have different resolutions and some curious points or lines are seen in enlarged photos because the axis and numbers are added later, so the resolution is different from the point area. We will try our best to avoid such misunderstandings in future image processing. Best regards, Lifeng Li. , 
 Hi, I am Dr Xu-Feng Huang from University of Wollongong Australia. Maybe we have the same name, but it was not me posted these comments. Please identify your self with your institution s name. I feel this is very odd who may have used my name to post these. Xu-Feng Huang , 
 Dear Jieyao Li, I did not make these comments. Someone has used my name to make somecomments over the last several days. It does not represent my view. Kind regards Dr Xu-Feng Huang University of Wollongong, Australia , 
 The gates are manually drawn, such as Fig. 2H. How the author guaranteed the same standard was used with such operation? ![file] In Fig. S1A, the axes are labelled at log format. But they should be in decimal format according to the distribution of flow dots. ![file] Moreover, there are image duplications in this publication. In Fig. 3A, at least 2 gel images are probably rotated and reused. ![file] ,