Liver fibrosis promotes immune escape in hepatocellular carcinoma via GOLM1-mediated PD-L1 upregulation.

Autor: Ke MY; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China., Xu T; Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250023, Shandong Province, China; Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250023, Shandong Province, China., Fang Y; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China., Ye YP; Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China., Li ZJ; Department of Neurosurgery, Anhui Provincial Hospital, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, Anhui Province, China., Ren FG; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China., Lu SY; Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China., Zhang XF; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China., Wu RQ; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China. Electronic address: rwu001@mail.xjtu.edu.cn., Lv Y; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China. Electronic address: luyi169@126.com., Dong J; Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China. Electronic address: dongjiandoctor@126.com.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2021 Aug 10; Vol. 513, pp. 14-25. Date of Electronic Publication: 2021 May 14.
DOI: 10.1016/j.canlet.2021.05.007
Abstrakt: Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8 + T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl 4 -induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl 4 -induced liver fibrosis. CD8 + T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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