Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer
© 2024 The Author(s)..
Background & Aims: The programmed death-ligand 1 (PD-L1) is a major co-inhibitory checkpoint factor that controls T-cell activities in tumours. PD-L1 is expressed on immune cells and tumour cells. Whether tumour cell-expressed PD-L1 affects tumour cells in an immune cell-independent fashion remains largely elusive. In this study, we investigated the significance of tumour cell-expressed PD-L1 with a focus on downstream signals and changes in lipid metabolism.
Methods: Immune-independent functions of PD-L1 in tumour growth were investigated in vitro and in immuno-deficient mice in vivo. The global influence of PD-L1 in targeted/untargeted lipidomic metabolites was studied by comprehensive mass spectrometry-based metabolomic analysis in liver cancer. Effects on lipid metabolism were confirmed by triglyceride and cholesterol assays as well as by Oil Red O staining in liver, pancreatic, breast, and oesophageal squamous cancer. Underlying mechanisms were investigated by real-time quantitative PCR, Western blot analysis, co-immunoprecipitation, pull-down assays, immunofluorescence staining, and RNA sequencing.
Results: PD-L1 enhanced the accumulation of triglycerides, cholesterol, and lipid droplets in tumours. PD-L1 influenced targeted/untargeted lipidomic metabolites in hepatoma, including lipid metabolism, glucose metabolism, amino acid metabolism, nucleotide metabolism, and energy metabolism, suggesting that PD-L1 globally modulates the metabolic reprogramming of tumours. Mechanistically, PD-L1 activated epidermal growth factor receptor (EGFR) and/or integrin β4 (ITGB4) by forming a complex of PD-L1/EGFR/ITGB4 in the cell membrane, prior to activating PI3K/mTOR/SREBP1c signalling, leading to reprogramming of lipid metabolism in tumours. Functionally, PD-L1-mediated lipid metabolism reprogramming supported the tumour growth in vitro and in vivo through EGFR and/or ITGB4 in an immune cell-independent manner.
Conclusions: Our findings on lipogenesis and EGFR activation by tumour cell-expressed PD-L1 suggest that, in addition to its immunostimulatory effects, anti-PD-L1 may restrict lipid metabolism and EGFR/ITGB4 signalling in liver cancer therapy.
Impact and implications: In this study, we present evidence that PD-L1 drives the reprogramming of lipid metabolism in tumours. PD-L1 forms a complex with epidermal growth factor receptor (EGFR) and ITGB4, activating the PI3K/Akt/mTOR/SREBP1c signalling pathway and thereby contributing to lipid metabolism in cancer progression. Our findings offer novel insights into the mechanisms by which PD-L1 initiates the reprogramming of lipid metabolism in tumours. From a clinical perspective, the anti-PD-L1 antibody may alleviate resistance to the anti-EGFR antibody cetuximab and inhibit the reprogramming of lipid metabolism in tumours.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
JHEP reports : innovation in hepatology - 6(2024), 4 vom: 29. März, Seite 101009 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhao, Man [VerfasserIn] |
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| Links: |
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| Themen: |
EGFR |
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| Anmerkungen: |
Date Revised 09.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.jhepr.2024.101009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369452143 |
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| 100 | 1 | |a Zhao, Man |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer |
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| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2024 The Author(s). | ||
| 520 | |a Background & Aims: The programmed death-ligand 1 (PD-L1) is a major co-inhibitory checkpoint factor that controls T-cell activities in tumours. PD-L1 is expressed on immune cells and tumour cells. Whether tumour cell-expressed PD-L1 affects tumour cells in an immune cell-independent fashion remains largely elusive. In this study, we investigated the significance of tumour cell-expressed PD-L1 with a focus on downstream signals and changes in lipid metabolism | ||
| 520 | |a Methods: Immune-independent functions of PD-L1 in tumour growth were investigated in vitro and in immuno-deficient mice in vivo. The global influence of PD-L1 in targeted/untargeted lipidomic metabolites was studied by comprehensive mass spectrometry-based metabolomic analysis in liver cancer. Effects on lipid metabolism were confirmed by triglyceride and cholesterol assays as well as by Oil Red O staining in liver, pancreatic, breast, and oesophageal squamous cancer. Underlying mechanisms were investigated by real-time quantitative PCR, Western blot analysis, co-immunoprecipitation, pull-down assays, immunofluorescence staining, and RNA sequencing | ||
| 520 | |a Results: PD-L1 enhanced the accumulation of triglycerides, cholesterol, and lipid droplets in tumours. PD-L1 influenced targeted/untargeted lipidomic metabolites in hepatoma, including lipid metabolism, glucose metabolism, amino acid metabolism, nucleotide metabolism, and energy metabolism, suggesting that PD-L1 globally modulates the metabolic reprogramming of tumours. Mechanistically, PD-L1 activated epidermal growth factor receptor (EGFR) and/or integrin β4 (ITGB4) by forming a complex of PD-L1/EGFR/ITGB4 in the cell membrane, prior to activating PI3K/mTOR/SREBP1c signalling, leading to reprogramming of lipid metabolism in tumours. Functionally, PD-L1-mediated lipid metabolism reprogramming supported the tumour growth in vitro and in vivo through EGFR and/or ITGB4 in an immune cell-independent manner | ||
| 520 | |a Conclusions: Our findings on lipogenesis and EGFR activation by tumour cell-expressed PD-L1 suggest that, in addition to its immunostimulatory effects, anti-PD-L1 may restrict lipid metabolism and EGFR/ITGB4 signalling in liver cancer therapy | ||
| 520 | |a Impact and implications: In this study, we present evidence that PD-L1 drives the reprogramming of lipid metabolism in tumours. PD-L1 forms a complex with epidermal growth factor receptor (EGFR) and ITGB4, activating the PI3K/Akt/mTOR/SREBP1c signalling pathway and thereby contributing to lipid metabolism in cancer progression. Our findings offer novel insights into the mechanisms by which PD-L1 initiates the reprogramming of lipid metabolism in tumours. From a clinical perspective, the anti-PD-L1 antibody may alleviate resistance to the anti-EGFR antibody cetuximab and inhibit the reprogramming of lipid metabolism in tumours | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a EGFR | |
| 650 | 4 | |a ITGB4 | |
| 650 | 4 | |a Lipid metabolism reprogramming | |
| 650 | 4 | |a PD-L1 | |
| 650 | 4 | |a SREBP1c | |
| 650 | 4 | |a Tumours | |
| 700 | 1 | |a Yuan, Hongfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Guang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yufei |e verfasserin |4 aut | |
| 700 | 1 | |a Bu, Yanan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Huihui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Pan |e verfasserin |4 aut | |
| 700 | 1 | |a Yun, Haolin |e verfasserin |4 aut | |
| 700 | 1 | |a Geng, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Jinyan |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Chunyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shuai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ningning |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaodong |e verfasserin |4 aut | |
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