title: Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma.
abstract: OBJECTIVE
  Tumor and viral antigens are expressed by hepatocellular carcinoma (HCC) in patients with chronic hepatitis B, but little is known about the immunodominance and function of tumor- and virus-specific CD8+ T cells in these patients.
  
  
  METHODS
  HLA-A2-restricted T-cell responses to 16 tumor antigens and hepatitis B virus (HBV) proteins were tested using 49 previously described epitopes. Cells from 30 HLA-A2+, HBV-infected patients (10 with HCC, 10 with HBV cirrhosis, and 10 HBV but no cirrhosis) were analyzed, after expansion, by enzyme-linked immunosorbent spot (ELISPOT). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 production, as well as expression of the degranulation marker CD107a on tumor-specific CD8+ T cells, were evaluated.
  
  
  RESULTS
  Cells from all groups had tumor-specific responses. The tumor antigens NY-ESO-1 and SSX-2 were most frequently targeted and were immunogenic in the HLA-A2 subtypes that are characteristic of Asian ethnicity. Tumor-specific T cells had low affinities; T cells from non-HCC patients were polyfunctional (IFN-gamma+, TNF-alpha+, CD107a+) and those from HCC patients displayed an exhausted phenotype (IFN-gamma+, CD107a+). Programmed Death 1 (PD-1) was expressed at higher levels on T cells from tumor and liver than peripheral blood from HCC patients and might contribute to T-cell exhaustion. Blocking PD-1/PD-L1 increased the frequency of tumor-specific T cells in HCC patients but did not restore T cell function.
  
  
  CONCLUSIONS
  Patients with or without HCC have a quantitative and functional hierarchy of tumor-specific T cells. HLA-A2-restricted T cells from HCC patients target NY-ESO-1, but exist in an exhausted state that might require additional activation to restore function.
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Gehring
authors.forename: Zi Zong
authors.initials: ZZ
authors.lastname: Ho
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Tan
authors.forename: Myat Oo
authors.initials: MO
authors.lastname: Aung
authors.forename: Kang Hoe
authors.initials: KH
authors.lastname: Lee
authors.forename: Kai Chah
authors.initials: KC
authors.lastname: Tan
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000821:virology; D000939:Epitopes / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000276:immunology* / Q000821:virology; D008113:Liver Neoplasms / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011336:Probability; D012016:Reference Values; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D000939:Epitopes; D015789:HLA-A2 Antigen