Metformin is a potential nontoxic adjuvant to enhance the efficacy of non-PDL1/PD-1 targeting immune therapies

초록

Investigations into various immunotherapies combined with conventional anticancer drugs are ongoing to increase therapeutic efficacy. However, combination therapy generally increases the risk of side effects. To achieve high efficacy with minimal side effects, nontoxic adjuvants should be identified and appropriate combinations should be designed based on the functional mechanism. In this regard, metformin can be an attractive candidate for immunotherapeutic adjuvants. Metformin is a widely used oral medication for type 2 diabetes (T2D) and has been recognized as a safe and well-tolerated drug through several decades of clinical experience. Interestingly, metformin also exhibits antitumor effects as several case-control studies for T2D patients indicated that metformin reduces the incidence of various cancer types. However, the functions and the detailed mechanism of metformin related to cancer immunity are not fully understood. In this study, we investigated the antitumor effects of metformin in relation to cancer immunity in the tumor microenvironment. Our data showed that AMPK activated by metformin decreases the expression of PD-L1 in the cancer cells, blocking PD-L1’s ability to aid cancer cells in escaping immune surveillance. This is caused by the mechanism in which phosphorylation of PD-L1 at S195 induces an abnormal glycan structure that leads to endoplasmic reticulum-associated degradation. In addition, we have obtained human breast tumor tissues from a previous clinical trial investigating metformin as treatment for breast cancer patients. The data from human tumor tissues also provided strong support to our current conclusion, namely AMPK activated by metformin reduces the level of PD-L1. On the basis of these results, we validated the possibility of metformin as an adjuvant to boost the efficacy of previous immunotherapy without toxicity. Our findings suggest that metformin has strong potential to be used as an adjuvant for immunotherapy.