title: Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma.
abstract: The role of CD4(+) cytotoxic T cells (CTLs) in hepatocellular carcinoma (HCC) remains obscure. This study characterized CD4(+) CTLs in HCC patients and further elucidated the associations between CD4(+) CTLs and HCC disease progression. In all, 547 HCC patients, 44 chronic hepatitis B (CHB) patients, 86 liver cirrhosis (LC) patients, and 88 healthy individuals were enrolled in the study. CD4(+) CTLs were defined by flow cytometry, immunohistochemistry, and lytic granule exocytosis assays. A multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Circulating and liver-infiltrating CD4(+) CTLs were found to be significantly increased in HCC patients during early stage disease, but decreased in progressive stages of HCC. This loss of CD4(+) CTLs was significantly correlated with high mortality rates and reduced survival time of HCC patients. In addition, the proliferation, degranulation, and production of granzyme A, granzyme B, and perforin of CD4(+) CTLs were inhibited by the increased forkhead/winged helix transcription factor (FoxP3(+) ) regulatory T cells in these HCC patients. Further analysis showed that both circulating and tumor-infiltrating CD4(+) CTLs were independent predictors of disease-free survival and overall survival after the resection of the HCC.
  
  
  CONCLUSIONS
  The progressive deficit in CD4(+) CTLs induced by increased FoxP3(+) regulatory T cells was correlated with poor survival and high recurrence rates in HCC patients. These data suggest that CD4(+) CTLs may represent both a potential prognostic marker and a therapeutic target for the treatment of HCC.
authors.affiliation: Research Center for Biological Therapy, Beijing 302 Hospital, Peking University Health Science Center, Beijing, China.
authors.forename: Junliang
authors.initials: J
authors.lastname: Fu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Qi
authors.forename: Shaojun
authors.initials: S
authors.lastname: Xing
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lv
authors.forename: Jianfei
authors.initials: J
authors.lastname: Shi
authors.forename: Baoyun
authors.initials: B
authors.lastname: Fu
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Liu
authors.forename: Ji-Yuan
authors.initials: JY
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Yulai
authors.initials: Y
authors.lastname: Zhao
authors.forename: George K K
authors.initials: GK
authors.lastname: Lau
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zhao
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Wang
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D053804:Granzymes / Q000096:biosynthesis; D019694:Hepatitis B, Chronic / Q000150:complications / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology; D008297:Male; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis; D011379:Prognosis; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes