In China, the incidence and mortality of hepatocellular carcinoma (HCC) are ranked third and second, respectively, and the new cases of HCC in China account for more than 50% of worldwide incidence. In China, about 70 million people are infected with hepatitis B virus (HBV), and more than 80% of liver cancer is caused by HBV. HBV-associated HCC is often accompanied by severe vascular invasion and portal vein tumor thrombus leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure.

Prof. YANG Pengyuan and Prof. WANG Fan, at the Institute of Biophysics (IBP), Chinese Academy of Science (CAS), revealed how HBV infection induced HCC venous metastasis and immune escape through a chemokine-based network. This research work entitled "Hepatitis B-induced IL-8 Promotes Hepatocellular Carcinoma Venous Metastasis and Intrahepatic Treg Accumulation" was published online in the journal Cancer Research on March 2, 2021.

The researchers firstly established a cytokines/chemokines array and screened the proinflammatory cytokine IL-8 as a potential target responsively to HBV infection. Mutiple models and mechanistic study further identified that HBV-induced IL-8 expression can be activated by HBx-mediated MEK-ERK signaling pathway, which enhanced permeability of the endothelium via endothelial CXCR1, the receptor of IL-8.

Based on the identification of IL-8-CXCR1 axis promoting tumor vascular metastasis in vivo, the researchers constructed a transgenic mouse that selectively express human CXCR1 in endothelial cells. Interestingly, the IL-8-CXCR1 axis on vascular endothelium dramatically increased liver tumorigenesis and metastasis, and the increase in lung metastasis was observed through overexpression of IL-8, but exogenous CXCR1 overexpression did not further enhance lung metastasis. Mechanistically, the IL-8-CXCR1 axis selectively induced GARP-latent-TGF-β in liver sinusoidal endothelial cells (LSECs) and subsequently provoked preferential regulatory T cell polarization to suppress antitumor immunity.

This study identifies a hepatitis B-induced IL-8/CXCR1/TGF-β signaling cascade that suppresses anti-tumor immunity and enhances metastasis in hepatocellular carcinoma, providing new potential targets for therapeutic intervention.

Figure1. Working model of IL-8-CXCR1 axis promoted venous metastasis and intrahepatic Treg accumulation in HBV-associated HCC

(Image by Dr. YANG Pengyuan's group)

This project was supported by the National Nature Science Foundation of China and Chinese Academy of Sciences.

Article link: https://cancerres.aacrjournals.org/content/early/2021/03/02/0008-5472.CAN-20-3453

Contact: YANG Pengyuan

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: pyyang@ibp.ac.cn

(Reported by Dr. YANG Pengyuan's group)