Hepatitis B virus promotes hepatocellular carcinoma (liver cancer) by modulating the immune response to environmental carcinogens

Hepatitis B virus (HBV) infection is a globally significant threaten to global health, with the potential to progress to hepatitis and hepatocellular carcinoma (HCC). Despite the availability of a vaccine, a population with non-responders, emphasizing the need for continued research into HBV-mediated immune responses. Interleukin-33 (IL-33) has emerged as a pivotal player in chronic inflammation and cancer, yet its role in specific viral contexts remains elusive. Here, we demonstrate the immune mechanisms underlying HBV infection and its contribution to HCC development. HBV with liver carcinogens induced IL-33 expression. Utilizing IL-33 and ST2 knockout mice, we demonstrate impaired HBV- mediated tumor progression, highlighting the critical involvement of IL-33 axis. Furthermore, we identify ST2 positive regulatory T cells (Treg) is a major effector cells with IL-33 in HBV-infected mice. ST2-deficient Tregs triggers immune cell infiltration, accompanied by reduced expression of immunosuppressive cytokines such as IL-10. Blocking this axis with STATIN, IL-33 inhibitor, shows promise therapeutic drug in chronic hepatitis and HCC in human subjects. In conclusion, our study reveals that IL-33/Treg axis as a critical mediator in hepatitis and its cancer development. Whole liver RNA sequencing was performed on HBV-DEN and Sham-DEN mice at this time point. HBV-DEN group showed positive upregulation of hepatitis related genes compared to Sham-DEN mice by Gene Set Enrichment Analysis

乙型肝炎病毒（Hepatitis B virus, HBV）感染是全球范围内严重威胁公共健康的重大卫生问题，其感染可进展为肝炎及肝细胞癌（hepatocellular carcinoma, HCC）。尽管已有预防性疫苗获批应用，但仍存在疫苗无应答人群，这凸显了持续开展HBV介导的免疫应答相关研究的必要性。白细胞介素33（Interleukin-33, IL-33）已被证实为慢性炎症与肿瘤发生发展中的关键调控因子，但其在特定病毒感染情境中的作用仍未明确。本研究阐明了HBV感染的免疫机制及其在HCC发生发展中的作用：HBV联合肝致癌物可诱导IL-33的表达。通过构建IL-33及ST2基因敲除小鼠模型，本研究证实HBV介导的肿瘤进展受到显著抑制，凸显了IL-33信号轴的关键调控作用。进一步研究发现，在HBV感染小鼠体内，ST2阳性调节性T细胞（regulatory T cells, Treg）是与IL-33协同发挥功能的主要效应细胞。ST2缺陷的Treg可促进免疫细胞浸润，并伴随白细胞介素10（Interleukin-10, IL-10）等免疫抑制细胞因子的表达水平下调。采用IL-33抑制剂司他丁（STATIN）阻断该信号轴，在慢性肝炎及HCC患者中展现出潜在的治疗应用前景。综上，本研究揭示IL-33/Treg信号轴是肝炎及其癌变进程的关键介导因子。本研究于指定时间点对HBV-DEN及Sham-DEN小鼠开展了全肝RNA测序，经基因集富集分析（Gene Set Enrichment Analysis, GSEA）验证，相较于Sham-DEN小鼠，HBV-DEN组小鼠的肝炎相关基因呈现显著上调表达。