Metformin promotes antitumor immunity via endoplasmic reticulum-associated degradation of PD-L1

By Jong-Ho Cha, Wen-Hao Yang, W. Xia, Yongkun Wei, Li-Chuan Chan, Seung-Oe Lim, Chia‐Wei Li, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee and 18 more. Molecules and Cells, 2018

690 citations recorded by the source corpus.

Summary 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 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 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.

Subfields: Epidemiology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/8947e1624be74884c8a0351a715afaf3fb88b6d0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

1. Jong-Ho Cha
2. Li-Chuan Chan
3. Ming-zhu Jin
4. J. Hsu
5. Wei-Lin Jin
6. Chia‐Wei Li
7. M. Hung

Citations in the corpus

• Mechanisms controlling PD-L1 expression in cancer (2019, background): “The accumulated PD-L1 is no longer transported to the Golgi and subsequently degraded via ER-associated protein degradation (ERAD) (Cha et al., 2018).”
• The updated landscape of tumor microenvironment and drug repurposing (2020, background): “AMPK activation further induces endoplasmic reticulum accumulation, endoplasmic reticulum-associated degradation, and decrease in PD-L1 level through PD-L1 phosphorylation and subsequent glycosylation.(219) Tumor-infiltrating cytotoxic T cells are correlated with better prognosis in breast cancer.”