Fu Junliang, Xu Dongping, Liu Zhenwen, Shi Ming, Zhao Ping, Fu Baoyun, Zhang Zheng, Yang Huiyin, Zhang Hui, Zhou Chunbao, Yao Jinxia, Jin Lei, Wang Huifen, Yang Yongping, Fu Yang-Xing, Wang Fu-Sheng
Research Center for Biological Therapy, Beijing Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Gastroenterology. 2007 Jun;132(7):2328-39. doi: 10.1053/j.gastro.2007.03.102. Epub 2007 Apr 14.
BACKGROUND & AIMS: Recent studies have suggested that CD4(+)CD25(+) regulatory T cells (Treg) are increased and linked to compromised immune responses in patients with hepatocellular carcinoma (HCC). This study attempted to further characterize CD4(+)CD25(+) forkhead/winged helix transcription factor (FoxP3)(+) Treg in blood, tumor, and nontumor liver tissues of HCC patients, and to understand how the Treg affects immune responses and contributes to disease progression.
A total of 123 HCC patients with chronic hepatitis B virus (HBV) infection, 21 HBV-related liver cirrhosis (LC) patients, and 47 normal controls were enrolled randomly. Flow cytometric, immunohistochemical, and immunosuppressive assays were used for analyses of properties of Treg. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model.
Circulating CD4(+)CD25(+)FoxP3(+) Treg frequency was increased significantly and correlated with disease progression in HCC patients. An abundant accumulation of Treg concurrent with significantly reduced infiltration of CD8(+) T cells was found in tumor regions compared with nontumor regions. Expression of granzyme A, granzyme B, and perforin was decreased dramatically in tumor-infiltrating CD8(+) T cells. Furthermore, Treg of HCC patients inhibited proliferation, activation, degranulation, and production of granzyme A, granzyme B, and perforin of CD8(+) T cells induced by anti-CD3/CD28 antibodies. Importantly, an increased quantity of circulating Treg was associated with high mortality and reduced survival time of HCC patients.
Increased CD4(+)CD25(+)FoxP3(+) Treg may impair the effector function of CD8(+) T cells, promote disease progression, and represent both a potential prognostic marker and a therapeutic target for HBV-related HCC individuals.
近期研究表明，在肝细胞癌（HCC）患者中，CD4(+)CD25(+)调节性T细胞（Treg）数量增加，且与免疫反应受损有关。本研究试图进一步描述HCC患者血液、肿瘤及非肿瘤肝组织中CD4(+)CD25(+)叉头/翼状螺旋转录因子（FoxP3）(+) Treg的特征，并了解Treg如何影响免疫反应及促进疾病进展。
随机纳入123例慢性乙型肝炎病毒（HBV）感染的HCC患者、21例HBV相关肝硬化（LC）患者及47例正常对照。采用流式细胞术、免疫组织化学及免疫抑制试验分析Treg的特性。使用Cox比例风险模型对总生存的预后因素进行多变量分析。
HCC患者循环CD4(+)CD25(+)FoxP3(+) Treg频率显著增加，且与疾病进展相关。与非肿瘤区域相比，肿瘤区域发现Treg大量积聚，同时CD8(+) T细胞浸润显著减少。肿瘤浸润CD8(+) T细胞中颗粒酶A、颗粒酶B和穿孔素的表达显著降低。此外，HCC患者的Treg抑制抗CD3/CD28抗体诱导的CD8(+) T细胞的增殖、活化、脱颗粒以及颗粒酶A、颗粒酶B和穿孔素的产生。重要的是，循环Treg数量增加与HCC患者高死亡率及生存时间缩短相关。
CD4(+)CD25(+)FoxP3(+) Treg增加可能损害CD8(+) T细胞的效应功能，促进疾病进展，并且是HBV相关HCC个体潜在的预后标志物和治疗靶点。
