title: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.
abstract: OBJECTIVE
  To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection.
  
  
  METHODS
  CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.
  
  
  RESULTS
  CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031).
  
  
  CONCLUSIONS
  Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.
authors.affiliation: Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, the Chinese Ministry of Education, Shanghai, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.forename: Shuang-Jian
authors.initials: SJ
authors.lastname: Qiu
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Wang
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Xiao
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Li
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000601:surgery; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000276:immunology* / Q000601:surgery; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000276:immunology; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*