Abstract A16: Metformin is a potential nontoxic adjuvant to enhance the efficacy of non-PDL1/PD-1 targeting immune therapies
Authors: Cha Jong-Ho , Yang Wen-Hao , Xia Weiya , Wei Yongkun , Chan Li-Chuan , Lim Seung-Oe , Li Chia-Wei , Hsu Jennifer , Wang Hung-Ling , Kuo Chu-Wei , Chang Wei-Chao , Hadad Sirwan , Purdie Colin , McCoy Aaron , Litton Jennifer , Mittendorf Elizabeth , Moulder Stacy , Symmans William , Thompson Alastair M , Piwnica-Worms Helen , Chen Chung-Hsuan , Khoo Kay-Hooi , Hung Mien-Chie 
Published: June 2021

Abstract
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. Metformin is expected to have synergistic effect with various non-PDL1/PD-1 targeting immune therapies without additional toxicity.
Citation Format: Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Yongkun Wei, Li-Chuan Chan, Seung-Oe Lim, Chia-Wei Li, Jennifer Hsu, Hung-Ling Wang, Chu-Wei Kuo, Wei-Chao Chang, Sirwan Hadad, Colin Purdie, Aaron McCoy, Jennifer Litton, Elizabeth Mittendorf, Stacy Moulder, William Symmans, Alastair M Thompson, Helen Piwnica-Worms, Chung-Hsuan Chen, Kay-Hooi Khoo, Mien-Chie Hung. Metformin is a potential nontoxic adjuvant to enhance the efficacy of non-PDL1/PD-1 targeting immune therapies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A16.