Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner

Wenjiao Xia; Xin Qi; Mingfeng Li; Yu Wu; Lulu Sun; Xinglong Fan; Yuan Yuan; Jing Li

doi:10.1080/2162402X.2021.1995999

Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner

Oncoimmunology. 2021 Oct 29;10(1):1995999. doi: 10.1080/2162402X.2021.1995999. eCollection 2021.

Authors

Wenjiao Xia¹, Xin Qi¹, Mingfeng Li¹, Yu Wu¹, Lulu Sun¹, Xinglong Fan², Yuan Yuan³, Jing Li^{1

4}

Affiliations

¹ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, P. R. China.
² Department of Thoracic Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
³ Department of Laboratory, Yushan Campus Hospital, Hospital of Ocean University of China, Qingdao, P. R. China.
⁴ Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, P. R. China.

Abstract

Metformin, a drug prescribed to treat type 2 diabetes, has been reported to possess antitumor activity via immunity activation. However, the influence of metformin on natural killer (NK) cells is not fully understood. Here, we investigated whether metformin exerts a potent anticancer effect by activating NK cells. The results showed that sustained exposure to metformin enhances the cytolytic activity of NK-92 cells. Moreover, this enhancement of cytotoxicity by metformin was also observed in NK cells from healthy peripheral blood and cancer patient ascites. Mechanistically, metformin induced activation of the JAK1/2/3/STAT5 and AKT/mTOR pathways in a p38 MAPK-dependent manner rather than an AMPK-dependent manner. In vivo experiments, metformin also improved cancer surveillance of NK cells in mouse models of lymphoma clearance and metastatic melanoma. Additionally, combination treatment with metformin and anti-PD-1 antibodies increased the therapy response rates of B16F10 melanoma. Moreover, metformin treatment increased NK cell and T cell infiltration in tumors. Therefore, these results provide a deeper understanding of metformin on the effector function of NK cells and will contribute to the development and applications of metformin in cancer treatment strategies.

Keywords: Metformin; NK cells; cancer surveillance; immunotherapy; p38 MAPK.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Type 2*
Killer Cells, Natural
Melanoma*
Metformin* / pharmacology
Metformin* / therapeutic use
Mice
p38 Mitogen-Activated Protein Kinases

Substances

Metformin
p38 Mitogen-Activated Protein Kinases

Grants and funding

This work was supported by the the NSFC Shandong Joint Fund [U1606403]; the National Natural Science Foundation of China [No. 81673450]; the State Key Program of National Natural Science of China [82030074]; Qingdao National Laboratory for Marine Science and Technology [No. 2015ASKJ02]; the National Science and Technology Major Project for Significant New Drugs Development [2018ZX09735-004]; Shandong Provincial Natural Science Foundation [ZR2019ZD18]; the NSFC-Shandong Joint Fund [U1906212].