研究人员揭示了乙型肝炎引起的肝癌静脉转移和免疫逃逸的

StephenW

Researchers reveal mechanism of hepatitis B-induced venous metastasis and immune escape of hepatocellular carcinoma

by Liu Jia, Chinese Academy of Sciences
Working model of IL-8-CXCR1 axis promoted venous metastasis and intrahepatic Treg accumulation in HBV-associated HCC. Credit: Dr. YANG Pengyuan's group

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 hepatocellular carcinoma (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.

In a study published in Cancer Research, Prof. Yang Pengyuan and Prof. Wang Fan at the Institute of Biophysics (IBP) of the Chinese Academy of Sciences (CAS) revealed how HBV infection induced HCC venous metastasis and immune escape through a chemokine-based network.

The researchers first established a cytokines/chemokines array and screened the proinflammatory cytokine IL-8 as a potential target responsively to HBV infection. Multiple models and mechanistic study 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, they then constructed a transgenic mouse that selectively express human CXCR1 in endothelial cells.

Interestingly, the IL-8-CXCR1 axis on the 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.

StephenW

研究人员揭示了乙型肝炎引起的肝癌静脉转移和免疫逃逸的机制

中国科学院刘佳
IL-8-CXCR1轴的工作模型促进了HBV相关肝癌的静脉转移和肝内Treg积累。图片来源：杨鹏远博士

在中国，约有7000万人感染了乙肝病毒（HBV），其中80％以上的肝癌是由HBV引起的。

HBV相关的肝细胞癌（HCC）通常伴有严重的血管浸润和门静脉肿瘤血栓，导致不良预后。但是，这种疾病的潜在机制仍然不清楚。

在《癌症研究》上发表的一项研究中，中国科学院生物物理研究所（IBP）的杨鹏远教授和王帆教授揭示了HBV感染如何通过基于趋化因子的药物诱导HCC静脉转移和免疫逃逸网络。

研究人员首先建立了细胞因子/趋化因子阵列，并筛选了促炎细胞因子IL-8作为对HBV感染作出反应的潜在靶标。多种模型和机理研究表明，HBx介导的MEK-ERK信号通路可以激活HBV诱导的IL-8表达，该通路通过IL-8受体内皮CXCR1增强内皮通透性。

基于对体内促进肿瘤血管转移的IL-8-CXCR1轴的鉴定，他们随后构建了在内皮细胞中选择性表达人CXCR1的转基因小鼠。

有趣的是，血管内皮上的IL-8-CXCR1轴显着增加了肝癌的发生和转移，并且通过IL-8的过表达观察到了肺转移的增加，但是外源性CXCR1的过表达并没有进一步增强肺转移。从机制上讲，IL-8-CXCR1轴选择性地诱导肝窦内皮细胞（LSEC）中的GARP潜伏性TGF-β，随后引发了优先调节性T细胞极化，从而抑制了抗肿瘤免疫力。

这项研究确定了乙型肝炎诱导的IL-8 / CXCR1 /TGF-β信号传导级联，该信号级联抑制抗肿瘤免疫力并增强肝细胞癌的转移，为治疗干预提供了新的潜在靶点。

StephenW

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