title: Recurrent hepatocellular carcinoma cells with stem cell-like properties: possible targets for immunotherapy.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) recurs with high frequency. Characterization of recurrent HCC cells will facilitate the design of future therapeutic strategies for recurrent HCC.
  
  
  METHODS
  Two cell lines, Hep-11 and Hep-12, were established from the same HCC patient's primary and recurrent tumor tissues, respectively, and then analyzed for stem cell-like properties, immune evasion strategies and immunogenicity.
  
  
  RESULTS
  Compared with Hep-11 cells, Hep-12 cells expressed higher levels of liver progenitor cell makers and displayed persistent tumorigenic potential in the serial transplantation assay. Although Hep-12 cells down-regulated human leukocyte antigen (HLA) class I expression, they could still be recognized and killed by autologous-activated tumor-infiltrating lymphocytes (TIL) in vitro. Pre-treatment with cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) increased the expression of HLA class I molecules on Hep-12 cells, and rendered them more susceptible to CD8(+) T-cell-mediated recognition and TIL-mediated cytotoxicity in vitro.
  
  
  CONCLUSIONS
  Our results indicate that Hep-12 cells possess stem cell-like properties, are susceptible to autologous-activated TIL-mediated recognition and cytotoxicity, and pre-treatment with TNF-alpha and IFN-gamma enhances their immunogenicity. This is the first evidence to support the hypothesis that immunotherapy can be used to target recurrent HCC cells with stem cell-like properties. This strategy may be an effective therapeutic approach to prevent HCC recurrence and control recurrent HCC growth.
authors.affiliation: National Key Laboratory of Protein Engineering and Plant Gene Engineering, Institute of Life Science, Peking University, Beijing, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Xu
authors.forename: Baocai
authors.initials: B
authors.lastname: Xing
authors.forename: Meihao
authors.initials: M
authors.lastname: Hu
authors.forename: Zuoliang
authors.initials: Z
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Xie
authors.forename: Guanghai
authors.initials: G
authors.lastname: Dai
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control / Q000628:therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D057075:Enzyme Assays; D006801:Humans; D057131:Immune Evasion / Q000276:immunology; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology*; D012008:Recurrence; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D052118:Lysosomal-Associated Membrane Protein 1; D007770:L-Lactate Dehydrogenase