Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients.
OBJECTIVE
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.
Fu
Junliang
J
Research Center for Biological Therapy, Beijing Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Xu
Dongping
D
Liu
Zhenwen
Z
Shi
Ming
M
Zhao
Ping
P
Fu
Baoyun
B
Zhang
Zheng
Z
Yang
Huiyin
H
Zhang
Hui
H
Zhou
Chunbao
C
Yao
Jinxia
J
Jin
Lei
L
Wang
Huifen
H
Yang
Yongping
Y
Fu
Yang-Xing
YX
Wang
Fu-Sheng
FS
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D015550:Cell Degranulation; D049109:Cell Proliferation; D016207:Cytokines / Q000037:antagonists & inhibitors; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D011379:Prognosis; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes