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 Litton; Elizabeth A Mittendorf; Stacy L Moulder; William F Symmans; Alastair M Thompson; Helen Piwnica-Worms; Chung-Hsuan Chen; Kay-Hooi Khoo; Mien-Chie Hung

doi:10.1016/j.molcel.2018.07.030

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 (Lead / Corresponding author)

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590 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 language	English
Pages (from-to)	606-620.e7
Number of pages	15
Journal	Molecular Cell
Volume	71
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2018.07.030
Publication status	Published - 16 Aug 2018

Keywords

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

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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

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title = "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.",

keywords = "cancer immunotherapy, ER accumulation, ERAD, glycosylation, immune checkpoint blockade, metformin, PD-L1",

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

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doi = "10.1016/j.molcel.2018.07.030",

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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, JL, Wang, H-L, Kuo, C-W, Chang, W-C, Hadad, S, Purdie, CA, McCoy, AM, Cai, S, Tu, Y, Litton, JK, Mittendorf, EA, Moulder, SL, Symmans, WF, Thompson, AM, Piwnica-Worms, H, Chen, C-H, Khoo, K-H & Hung, M-C 2018, 'Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1', Molecular Cell, vol. 71, no. 4, pp. 606-620.e7. https://doi.org/10.1016/j.molcel.2018.07.030

TY - JOUR

T1 - Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1

AU - Cha, Jong-Ho

AU - Yang, Wen-Hao

AU - Xia, Weiya

AU - Wei, Yongkun

AU - Chan, Li-Chuan

AU - Lim, Seung-Oe

AU - Li, Chia-Wei

AU - Kim, Taewan

AU - Chang, Shih-Shin

AU - Lee, Heng-Huan

AU - Hsu, Jennifer L

AU - Wang, Hung-Ling

AU - Kuo, Chu-Wei

AU - Chang, Wei-Chao

AU - Hadad, Sirwan

AU - Purdie, Colin A

AU - McCoy, Aaron M

AU - Cai, Shirong

AU - Tu, Yizheng

AU - Litton, Jennifer K

AU - Mittendorf, Elizabeth A

AU - Moulder, Stacy L

AU - Symmans, William F

AU - Thompson, Alastair M

AU - Piwnica-Worms, Helen

AU - Chen, Chung-Hsuan

AU - Khoo, Kay-Hooi

AU - Hung, Mien-Chie

PY - 2018/8/16

Y1 - 2018/8/16

N2 - 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.

AB - 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.

KW - cancer immunotherapy

KW - ER accumulation

KW - ERAD

KW - glycosylation

KW - immune checkpoint blockade

KW - metformin

KW - PD-L1

U2 - 10.1016/j.molcel.2018.07.030

DO - 10.1016/j.molcel.2018.07.030

M3 - Article

C2 - 30118680

SN - 1097-2765

VL - 71

SP - 606-620.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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