Metformin Enhances the Antitumor Activity of CD8+ T Lymphocytes via the AMPK–miR-107–Eomes–PD-1 Pathway
Zhen Zhang, Feng Li, Yonggui Tian, Ling Cao, Qun Gao, Chaoqi Zhang, Kai Zhang, Chunyi Shen, Ping Yu, Nomathamsanqa Resegofetse Maimela, Liping Wang, Bin Zhang, Yi Zhang
Abstract
Abstract Metformin has been studied for its anticancer effects by regulating T cell functions. However, the mechanisms through which metformin stimulates the differentiation of memory T cells remain unclear. We found that the frequencies of memory stem and central memory T cells increased for both in peripheral and tumor-infiltrating CD8+ T cells in metformin-treated lung cancer patients compared with those not taking the medication. An in vitro assay showed that metformin promoted the formation of memory CD8+ T cells and enhanced their antiapoptotic abilities. In addition, AMP-activated protein kinase (AMPK) activation decreased microRNA-107 expression, thus enhancing Eomesodermin expression, which suppressed the transcription of PDCD1 in metformin-treated CD8+ T cells. In the CAR-T cell therapy model, metformin also exhibited cytotoxicity-promoting effects that led to decreased tumor growth. Metformin could reprogram the differentiation of CD8+ T cells, which may benefit the clinical therapy of cancer patients by facilitating long-lasting cytotoxic functions.