Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, Guangdong, China.
Front Immunol. 2023 Apr 3;14:1079495. doi: 10.3389/fimmu.2023.1079495. eCollection 2023.
Liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. As a chronic liver disease, many studies have shown that the immune response plays a key role in the progression of liver cancer. Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for HCC, accounting for 50%-80% of HCC cases worldwide, and little is known about the immune status of HBV associated hepatocellular carcinoma (HBV-HCC), therefore, we aimed to explore the changes in peripheral immunity in patients with HBV-HCC.
In this study, patients with HBV-HCC (n=26), patients with hepatitis B-related cirrhosis (HBV-LC) (n=31) and healthy volunteers (n=49) were included. The lymphocytes and their subpopulation phenotypes in peripheral blood were characterized. In addition, we explored the effect of viral replication on peripheral immunity in patients with HCC and analyzed the circulating immunophenotypic characteristics at different stages of HCC with flow cytometry.
Firstly, our results showed that the percentages of total αβ T cells in the peripheral blood of HBV-HCC patients was significantly decreased compared to healthy subjects. Secondly, we found that naïve CD4 T cells in HBV-HCC patients were significantly reduced, terminally differentiated CD8 T cells, homing memory CD8 T cells and Th2 cells were increased in peripheral circulation in HBV-HCC patients. Moreover, in the peripheral blood of HBV-HCC patients, expression of TIGIT on CD4 T cells and PD-1 on the surface of Vδ 1 T cells was increased. In addition, we found that sustained viral replication resulted in up-regulation of TIM3 expression on CD4 T cells, and TIM3 γδ T cells increased in peripheral circulation in patients with advanced HBV-HCC.
Our study showed that circulating lymphocytes in HBV-HCC patients exhibited features of immune exhaustion, especially in HCC patients with persistent viral replication and in patients with intermediate and advanced HBV-HCC, including decreased frequency of T cells and elevated expression of inhibitory receptors including TIGIT and TIM3 on CD4 T cells and γδ T cells. Meanwhile, our research suggests that the combination of CD3 T cell and CD8HLADRCD38 T cell may be a potential diagnostic indicator for HBV-HCC. These findings could help us to better understand the immune characteristics of HBV-HCC and explore the immune mechanisms and immunotherapy strategies for HBV-HCC.
肝癌是全球第六大常见癌症，也是癌症相关死亡的第三大主要原因。作为一种慢性肝病，许多研究表明免疫反应在肝癌的进展中起着关键作用。慢性乙型肝炎病毒（HBV）感染是 HCC 的高危因素之一，占全球 HCC 病例的 50%-80%，而对于 HBV 相关肝细胞癌（HBV-HCC）的免疫状态知之甚少，因此，我们旨在探讨 HBV-HCC 患者外周免疫的变化。
本研究纳入了 26 例 HBV-HCC 患者、31 例乙型肝炎相关肝硬化（HBV-LC）患者和 49 名健康志愿者。对其外周血中的淋巴细胞及其亚群表型进行了特征分析。此外，我们还探讨了病毒复制对 HCC 患者外周免疫的影响，并通过流式细胞术分析了 HCC 不同阶段的循环免疫表型特征。
首先，我们的研究结果表明，HBV-HCC 患者外周血中总αβ T 细胞的百分比明显低于健康对照组。其次，我们发现 HBV-HCC 患者的 naïve CD4 T 细胞明显减少，终末分化的 CD8 T 细胞、归巢记忆 CD8 T 细胞和 Th2 细胞在外周循环中增加。此外，在 HBV-HCC 患者的外周血中，CD4 T 细胞上的 TIGIT 和 Vδ1T 细胞表面上的 PD-1 的表达增加。此外，我们发现持续的病毒复制导致 CD4 T 细胞上 TIM3 的表达上调，并且在晚期 HBV-HCC 患者的外周循环中，γδT 细胞增加。
我们的研究表明，HBV-HCC 患者的循环淋巴细胞表现出免疫衰竭的特征，特别是在持续性病毒复制的 HCC 患者和中晚期 HBV-HCC 患者中，包括 T 细胞频率降低和 CD4 T 细胞和 γδ T 细胞上抑制性受体（包括 TIGIT 和 TIM3）的表达升高。同时，我们的研究表明 CD3T 细胞和 CD8HLADRCD38T 细胞的组合可能是 HBV-HCC 的潜在诊断指标。这些发现有助于我们更好地了解 HBV-HCC 的免疫特征，并探索 HBV-HCC 的免疫机制和免疫治疗策略。
