Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1

Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Yongkun Wei, Li-Chuan Chan, Seung-Oe Lim, Chia-Wei Li, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Jennifer L Hsu, Hung-Ling Wang, Chu-Wei Kuo, Wei-Chao Chang, Sirwan Hadad, Colin A Purdie, Aaron M McCoy, Shirong Cai, Yizheng Tu, Jennifer K LittonElizabeth A Mittendorf, Stacy L Moulder, William F Symmans, Alastair M Thompson, Helen Piwnica-Worms, Chung-Hsuan Chen, Kay-Hooi Khoo, Mien-Chie Hung

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89 Citations (Scopus)

Abstract

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

Original languageEnglish
Pages (from-to)606-620.e7
Number of pages15
JournalMolecular Cell
Volume71
Issue number4
DOIs
Publication statusPublished - 16 Aug 2018

Keywords

  • cancer immunotherapy
  • ER accumulation
  • ERAD
  • glycosylation
  • immune checkpoint blockade
  • metformin
  • PD-L1

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    Cha, J-H., Yang, W-H., Xia, W., Wei, Y., Chan, L-C., Lim, S-O., Li, C-W., Kim, T., Chang, S-S., Lee, H-H., Hsu, J. L., Wang, H-L., Kuo, C-W., Chang, W-C., Hadad, S., Purdie, C. A., McCoy, A. M., Cai, S., Tu, Y., ... Hung, M-C. (2018). Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Molecular Cell, 71(4), 606-620.e7. https://doi.org/10.1016/j.molcel.2018.07.030