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

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Cha JH,Yang WH,Xia W,Wei Y,Chan LC,Lim SO,Li CW,Kim T,Chang SS,Lee HH,Hsu JL,Wang HL,Kuo CW,Chang WC,Hadad S,Purdie CA,McCoy AM,Cai S,Tu Y,Litton JK,Mittendorf EA,Moulder SL,Symmans WF,Thompson AM,Piwnica-

doi

10.1016/j.molcel.2018.07.030

subject

Has Abstract

pub_date

2018-08-16 00:00:00

pages

606-620.e7

issue

4

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(18)30599-9

journal_volume

71

pub_type

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