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Research
Jian Dong
First Affiliated Hospital of Xi'an jiaotong university
Corresponding Author
License:
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Background:
Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC) represent significant challenges in the application of this treatment. Liver cirrhosis is a key driver of tumor immune escape. However, the mechanism underlying this outcome has never been clarified. This study sought to explore the role of liver cirrhosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression.
Methods:
Ninety-nine fixed HCC tissue samples were used to analyze the association between liver cirrhosis and immune escape by immunohistochemistry. H22 cells with or without GOLM1 knockdown were inoculated subcutaneously into BALB/c and BALB/c-nu/nu mice. We also created hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) and induced chemical carcinogenesis. The efficacy of anti-PD-L1 therapy combined with GOLM1 inhibition was estimated in GOLM1 -overexpressing subcutaneous model of HCC.
Results:
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 CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with cirrhosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from Alb/GOLM1 mice 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.
Conclusions:
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.
Keywords
Liver cirrhosis, Hepatocellular Carcinoma, Immune Escape, GOLM1
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Jian Dong
First Affiliated Hospital of Xi'an jiaotong university
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 03 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background:
Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC) represent significant challenges in the application of this treatment. Liver cirrhosis is a key driver of tumor immune escape. However, the mechanism underlying this outcome has never been clarified. This study sought to explore the role of liver cirrhosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression.
Methods:
Ninety-nine fixed HCC tissue samples were used to analyze the association between liver cirrhosis and immune escape by immunohistochemistry. H22 cells with or without GOLM1 knockdown were inoculated subcutaneously into BALB/c and BALB/c-nu/nu mice. We also created hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) and induced chemical carcinogenesis. The efficacy of anti-PD-L1 therapy combined with GOLM1 inhibition was estimated in GOLM1 -overexpressing subcutaneous model of HCC.
Results:
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 CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with cirrhosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from Alb/GOLM1 mice 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.
Conclusions:
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
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