Cao Wei-Hua, Zhang Ya-Qin, Li Xin-Xin, Zhang Zi-Yu, Li Ming-Hui
Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Peking University Ditan Teaching Hospital, Beijing 100015, China.
World J Hepatol. 2024 Oct 27;16(10):1158-1168. doi: 10.4254/wjh.v16.i10.1158.
Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.
乙型肝炎病毒（HBV）感染在肝细胞癌（HCC）的发生发展中起重要作用，我国肝癌患者中HBV感染率高达92.05%。由于长期暴露于来自肠道的慢性抗原，肝脏需要维持一定水平的免疫耐受，既要避免非致病性抗原引起的严重炎症，又要保持对感染和肿瘤快速剧烈反应的可能性。因此，HBV感染通过高度复杂且相互交织的信号通路与肿瘤微环境（TME）相互作用，导致HCC中形成特殊的TME。由于TME的变化，肿瘤细胞可通过细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）抑制肿瘤特异性T细胞功能，从而逃避免疫监视。干扰素作为一类具有强大生物活性的免疫因子，可通过多种途径改善HBV-HCC的TME。近年来，HCC的系统治疗逐渐走出困境。除了不断涌现新的多靶点抗血管酪氨酸激酶抑制剂药物外，免疫检查点抑制剂为HCC的系统治疗开辟了新途径。目前，基于PD-1/L1抑制剂的免疫治疗已逐渐成为HCC系统治疗的新方向，全球临床研究纳入患者的疾病特征与中国患者不同。因此，我国一组预后较差的HBV背景HCC患者是否也能从免疫治疗中获益是一个备受关注的问题。本综述旨在阐明HBV相关HCC患者免疫治疗的进展，涉及：（1）基于干扰素的免疫治疗；（2）基于PD-1/L1抑制剂的免疫治疗；（3）基于CTLA4抑制剂的免疫治疗；（4）过继性细胞转移；（5）联合免疫治疗策略；（6）免疫治疗的不足。
