TY - JOUR
T1 - Increased Regulatory T Cells Correlate With CD8 T-Cell Impairment and Poor Survival in Hepatocellular Carcinoma Patients
AU - Fu, Junliang
AU - Xu, Dongping
AU - Liu, Zhenwen
AU - Shi, Ming
AU - Zhao, Ping
AU - Fu, Baoyun
AU - Zhang, Zheng
AU - Yang, Huiyin
AU - Zhang, Hui
AU - Zhou, Chunbao
AU - Yao, Jinxia
AU - Jin, Lei
AU - Wang, Huifen
AU - Yang, Yongping
AU - Fu, Yang Xing
AU - Wang, Fu Sheng
N1 - Funding Information:
Supported by a grant from the National Key Basic Research Program of China (2006CB504305), the National Youth Foundation of China (30525042), and the National Nature Science Foundation of China (30571738).
PY - 2007/6
Y1 - 2007/6
N2 - 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. Methods: 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. Results: 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. Conclusions: 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.
AB - 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. Methods: 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. Results: 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. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=34250005419&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250005419&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2007.03.102
DO - 10.1053/j.gastro.2007.03.102
M3 - Article
C2 - 17570208
AN - SCOPUS:34250005419
SN - 0016-5085
VL - 132
SP - 2328
EP - 2339
JO - Gastroenterology
JF - Gastroenterology
IS - 7
ER -