title: Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients.
abstract: 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.
authors.affiliation: Research Center for Biological Therapy, Beijing Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
authors.forename: Junliang
authors.initials: J
authors.lastname: Fu
authors.forename: Dongping
authors.initials: D
authors.lastname: Xu
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Baoyun
authors.initials: B
authors.lastname: Fu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Huiyin
authors.initials: H
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Chunbao
authors.initials: C
authors.lastname: Zhou
authors.forename: Jinxia
authors.initials: J
authors.lastname: Yao
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Huifen
authors.initials: H
authors.lastname: Wang
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Yang-Xing
authors.initials: YX
authors.lastname: Fu
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Wang
mesh_terms: 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*
chemical_list: 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