HBV感染在B细胞相关促肝癌转移中的作用及机制

Chronic hepatitis B virus (HBV) infection is the major cause of human hepatocellular carcinoma (HCC) in China. However, the role of active HBV infection in hepatoma progression remains unknown. We recently found that B cells constituted an important component of the leukocyte infiltrating in the hepatoma stroma. In HCC patients with persistent active HBV infection, B cells appeared to be activated, and the density of B cells in tumor tissue was positively correlated with recurrence and intrahepatic metastasis. These results indicated that active HBV replication may have synergistic effects on B cell-mediated metastasis in human HCC, although the detailed mechanism remains unclear.. Based on these findings, we will combine the clinical sample analysis and experimental studies to: 1). Examine the phenotype and evaluate the various potential functions of B cells in different situations of HBV infection, and reveal the underlying mechanism. 2). Characterize the specific nature of B cells in the context of HBV infection that determine their ability to facilitate tumor metastasis. 3). Investigate the impact of anti-virus therapy on the phenotype and function of B cells. The results obtained from this project will not only reveal the molecular mechanism about how B cells display their pro-tumorigenic functions in human hepatoma with active HBV infection, but also provide the molecular basis for the development of a potential novel strategy for cancer prevention and cure which targets HBV and B cells.

HBV感染是我国肝癌的重要致病因素，但HBV感染在肝癌进展过程中的作用及调控机制未完全清楚。我们前期观察到：B细胞是人肝癌癌旁间质的重要组分；在持续活跃HBV感染肝癌患者中，B细胞多呈现为活化状态，而且它们的浸润数量选择性与肝癌术后复发以及肝内转移呈正相关。提示：HBV的活跃复制很可能赋予了B细胞促肿瘤转移作用。以此为基础，本课题拟结合临床样本分析和实验模型，来深入研究不同HBV感染状态下对肿瘤浸润B细胞表型/功能的改变及潜在的调控机制，筛选出1-2个HBV感染过程中B细胞相关的促肿瘤转移因素；通过临床病例（肝癌及慢性乙型肝炎患者）回顾分析，探讨抗病毒治疗对B细胞表型/功能的影响，以及能否有效逆转B细胞介导的肿瘤复发；初步阐明HBV感染及B细胞浸润调控肝癌恶性进展的协同机制，为研制以HBV和B细胞为靶标的肿瘤分子分期标准和新型防治手段提供理论基础。

国内约80%的肝细胞肝癌（HCC）与乙型肝炎病毒（HBV）感染有关。目前，我们对HBV相关HCC中浆细胞亚群的组成、来源以及这些亚群对临床的影响知之甚少。在本项目研究中，我们发现HBV DNA载量与抗病毒治疗是中晚期HBV相关HCC长期生存的重要影响因素。我们还发现在HBV相关HCC的肿瘤组织中，B细胞表现出体基因高频突变和IgG转化重组。肿瘤中活化的CD4+T细胞，通过IFN-gamma促进肿瘤巨噬细胞表达、分泌CXCL10。CXCL10通过CXCR3诱导B细胞向IgG+浆细胞分化。IgG+浆细胞通过IgG激活巨噬细胞Fc受体，促进巨噬细胞分泌IL6、IL10及CCL20等促肿瘤因子。在小鼠模型中，清除B细胞可以阻止这类促肿瘤巨噬细胞的产生，促进T细胞的抗肿瘤功能，并能抑制肿瘤生长。与非肿瘤组织相比，人HCC和小鼠肝肿瘤组织中DNA甲基转移酶1和EZH2的表达显著上升。给小鼠注射GSK126和5-AZA-dC可以诱导肿瘤CXCL10的表达并促进浆细胞的分化，抑制肿瘤T细胞抗肿瘤功能，并促进肿瘤生长。而且，我们发现在HBV相关HCC组织中，B细胞，尤其是初始B细胞能够对Th细胞进行代谢重塑，从而启动辅助炎性Th亚群的极化。B细胞促进Th亚群极化的关键是ICOS-ICOSL信号轴介导的对糖的摄入与利用。而在此过程中，mTOR的激活对T细胞糖酵解起到重要作用。本项目的上述成果为通过干预浆细胞介导的免疫抑制来治疗HBV相关HCC提供了提供了重要的新思路。