Tumour Cell-expressed PD-L1 Reprograms Lipid Metabolism Via EGFR/ITGB4/SREBP1c Signalling in Liver Cancer

Overview

Journal JHEP Rep

Specialty Gastroenterology

Date 2024 Mar 8

PMID 38455469

Authors

Man Zhao

Hongfeng Yuan

Guang Yang

Yufei Wang

Yanan Bu

Huihui Zhang

Lina Zhao

Pan Lv

Haolin Yun

Yu Geng

Jinyan Feng

Chunyu Hou

Shuai Wang

Ningning Zhang

Wei Lu

Xiaodong Zhang

Affiliations

Soon will be listed here.

Abstract

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 and in immuno-deficient mice . 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 and 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.

Citing Articles

Multi-pathway oxidative stress amplification via controllably targeted nanomaterials for photoimmunotherapy of tumors.

Li S, Liu Y, Zhang X, Liu Y, Si L, Jiang S J Nanobiotechnology. 2025; 23(1):33.

PMID: 39844145 PMC: 11753039. DOI: 10.1186/s12951-025-03116-4.

References

Butler L, Perone Y, Dehairs J, Lupien L, de Laat V, Talebi A . Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev. 2020; 159:245-293. PMC: 7736102. DOI: 10.1016/j.addr.2020.07.013. View

Kalyankrishna S, Grandis J . Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006; 24(17):2666-72. DOI: 10.1200/JCO.2005.04.8306. View

Sun C, Mezzadra R, Schumacher T . Regulation and Function of the PD-L1 Checkpoint. Immunity. 2018; 48(3):434-452. PMC: 7116507. DOI: 10.1016/j.immuni.2018.03.014. View

Gobel A, Rauner M, Hofbauer L, Rachner T . Cholesterol and beyond - The role of the mevalonate pathway in cancer biology. Biochim Biophys Acta Rev Cancer. 2020; 1873(2):188351. DOI: 10.1016/j.bbcan.2020.188351. View

Ni H, Dydensborg A, Herring F, Basora N, Gagne D, Vachon P . Upregulation of a functional form of the beta4 integrin subunit in colorectal cancers correlates with c-Myc expression. Oncogene. 2005; 24(45):6820-9. DOI: 10.1038/sj.onc.1208848. View

Ying H, Zhang X, Duan Y, Lao M, Xu J, Yang H . Non-cytomembrane PD-L1: An atypical target for cancer. Pharmacol Res. 2021; 170:105741. DOI: 10.1016/j.phrs.2021.105741. View

Han J, Wang Y . mTORC1 signaling in hepatic lipid metabolism. Protein Cell. 2017; 9(2):145-151. PMC: 5818363. DOI: 10.1007/s13238-017-0409-3. View

Cui M, Xiao Z, Wang Y, Zheng M, Song T, Cai X . Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway. Cancer Res. 2015; 75(5):846-57. DOI: 10.1158/0008-5472.CAN-14-1192. View

Ribas A, Wolchok J . Cancer immunotherapy using checkpoint blockade. Science. 2018; 359(6382):1350-1355. PMC: 7391259. DOI: 10.1126/science.aar4060. View

10.

Hao Y, Li D, Xu Y, Ouyang J, Wang Y, Zhang Y . Investigation of lipid metabolism dysregulation and the effects on immune microenvironments in pan-cancer using multiple omics data. BMC Bioinformatics. 2019; 20(Suppl 7):195. PMC: 6509864. DOI: 10.1186/s12859-019-2734-4. View

11.

Leng C, Zhang Z, Chen W, Luo H, Song J, Dong W . An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK-AKT pathway. Cancer Lett. 2016; 376(1):188-96. DOI: 10.1016/j.canlet.2016.03.023. View

12.

Wang S, Li J, Xie J, Liu F, Duan Y, Wu Y . Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway. Oncogene. 2018; 37(30):4164-4180. DOI: 10.1038/s41388-018-0252-x. View

13.

Lee W, Chen W, Wang C, Lin W, Tseng T . Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and beta 4 integrin function in MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol. 2007; 226(2):178-91. DOI: 10.1016/j.taap.2007.09.013. View

14.

Goldberg R . Cetuximab. Nat Rev Drug Discov. 2005; Suppl:S10-1. DOI: 10.1038/nrd1728. View

15.

Zhang N, Zeng Y, Du W, Zhu J, Shen D, Liu Z . The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. Int J Oncol. 2016; 49(4):1360-8. DOI: 10.3892/ijo.2016.3632. View

16.

Pan Q, Zhong S, Wang H, Wang X, Li N, Li Y . The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability. Mol Cell. 2021; 81(13):2736-2751.e8. DOI: 10.1016/j.molcel.2021.04.009. View

17.

Mossmann D, Park S, Hall M . mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 2018; 18(12):744-757. DOI: 10.1038/s41568-018-0074-8. View

18.

Tai Y, Lai I, Peng Y, Ding S, Shen T . Activation of focal adhesion kinase through an interaction with β4 integrin contributes to tumorigenicity of colon cancer. FEBS Lett. 2016; 590(12):1826-37. DOI: 10.1002/1873-3468.12215. View

19.

Finley L . What is cancer metabolism?. Cell. 2023; 186(8):1670-1688. PMC: 10106389. DOI: 10.1016/j.cell.2023.01.038. View

20.

Roskoski Jr R . Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol Res. 2018; 139:395-411. DOI: 10.1016/j.phrs.2018.11.014. View