title: Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma.
abstract: Many tumor-associated antigens (TAAs) recognized by cytotoxic T cells (CTLs) have been identified during the last two decades and some of them have been used in clinical trials. However, there are very few in the field of immunotherapy for hepatocellular carcinoma (HCC) because there have not been comparative data regarding CTL responses to various TAAs. In the present study, using 27 peptides derived from 14 different TAAs, we performed comparative analysis of various TAA-specific T-cell responses in 31 HCC patients to select useful antigens for immunotherapy and examined the factors that affect the immune responses to determine a strategy for more effective therapy. Twenty-four of 31 (77.4%) HCC patients showed positive responses to at least one TAA-derived peptide in enzyme-linked immunospot assay. The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. HCC treatments enhanced TAA-specific immune responses with an increased number of memory T cells and induced de novo T-cell responses to lymphocyte-specific protein tyrosine kinase, human epidermal growth factor receptor type 2, p53, and hTERT. Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides.
  
  
  CONCLUSIONS
  Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Arai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Akito
authors.initials: A
authors.lastname: Sakai
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagaya
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D060908:CTLA-4 Antigen; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000628:therapy; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008113:Liver Neoplasms / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015843:Serpins; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019098:Telomerase; D016159:Tumor Suppressor Protein p53 / Q000276:immunology; D000509:alpha-Fetoproteins / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015843:Serpins; D019098:Telomerase; D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; C556706:CTLA4 protein, human; C051072:squamous cell carcinoma-related antigen; C114462:multidrug resistance-associated protein 3; C509186:TERT protein, human