Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan University, Zhuhai, Guangdong, China.
Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, China.
Clin Transl Med. 2024 Jul;14(7):e1731. doi: 10.1002/ctm2.1731.
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8 T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8 T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8 T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8 T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8 T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8 T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8 T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
乙型肝炎病毒 (HBV) 感染在肝脏相关疾病的病因和进展中起着重要作用，包括慢性肝炎、纤维化、肝硬化和最终的肝细胞癌 (HCC)。值得注意的是，HBV 感染是导致 HCC 发展的主要病因。鉴于 HBV 感染对肝脏疾病的重大贡献，全面了解肝脏微环境中的免疫动力学，涵盖慢性 HBV 感染、纤维化、肝硬化和 HCC，是至关重要的。在这篇综述中，我们重点讨论了从 HBV 感染到 HCC 的致病肝脏微环境中 CD8 T 细胞的功能改变。我们详细回顾了缺氧、酸性 pH 值、代谢重编程、氨基酸缺乏、抑制性检查点分子、免疫抑制细胞因子和肠道-肝脏通讯在塑造 CD8 T 细胞在肝脏微环境中的功能障碍中的作用。这些因素对临床预后有重大影响。此外，我们还全面回顾了基于 CD8 T 细胞的肝脏疾病治疗策略，包括 HBV 感染、纤维化、肝硬化和 HCC。这些策略包括免疫检查点阻断、代谢性 T 细胞靶向治疗、治疗性 T 细胞疫苗接种和过继转移基因工程 CD8 T 细胞，以及联合使用程序性细胞死亡蛋白-1/程序性死亡配体-1 (PD-1/PD-L1) 抑制剂与靶向线粒体的抗氧化剂。鉴于针对 HBV 诱导的肝细胞癌 (HBV + HCC) 不同阶段的 CD8 T 细胞具有潜力，我们回顾了目前需要研究阐明 CD8 T 细胞与肝脏微环境在 HBV 感染进展为 HCC 过程中的复杂相互作用。我们还讨论了个性化治疗方案，结合治疗策略和利用肠道微生物群调节，这可能带来更好的临床获益。总之，本文深入探讨了慢性 HBV 感染、HCC 进展和相关肝脏疾病中 CD8 T 细胞在肝脏中的免疫动力学、微环境变化和治疗策略。
