Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma.
Human telomerase reverse transcriptase, hTERT, has been identified as the catalytic enzyme required for telomere elongation. hTERT is expressed in most tumor cells but seldom expressed in most human adult cells. It has been reported that 80% to 90% of hepatocellular carcinomas (HCCs) express hTERT, making the enzyme a potential target in immunotherapy for HCC. In the current study, we identified hTERT-derived, HLA-A*2402-restricted cytotoxic T cell (CTL) epitopes and analyzed hTERT-specific CTL responses in patients with HCC. Peptides containing the epitopes showed high affinity to bind HLA-A*2402 in a major histocompatibility complex binding assay and were able to induce hTERT-specific CTLs in both hTERT cDNA-immunized HLA-A*2402/Kb transgenic mice and patients with HCC. The CTLs were able to kill hepatoma cell lines depending on hTERT expression levels in an HLA-A*2402-restricted manner and induced irrespective of hepatitis viral infection. The number of single hTERT epitope-specific T cells detected by ELISPOT assay was 10 to 100 specific cells per 3 x 10(5) PBMCs, and positive T cell responses were observed in 6.9% to 12.5% of HCC patients. hTERT-specific T cell responses were observed even in the patients with early stages of HCC. The frequency of hTERT/tetramer+ CD8+ T cells in the tumor tissue of patients with HCC was quite high, and they were functional. In conclusion, these results suggest that hTERT is an attractive target for T-cell-based immunotherapy for HCC, and the identified hTERT epitopes may be valuable both for immunotherapy and for analyzing host immune responses to HCC.
Mizukoshi
Eishiro
E
Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Nakamoto
Yasunari
Y
Marukawa
Yohei
Y
Arai
Kuniaki
K
Yamashita
Tatsuya
T
Tsuji
Hirokazu
H
Kuzushima
Kiyotaka
K
Takiguchi
Masafumi
M
Kaneko
Shuichi
S
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000032:analysis; D004268:DNA-Binding Proteins / Q000276:immunology / Q000494:pharmacology*; D004195:Disease Models, Animal; D000939:Epitopes; D005260:Female; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011336:Probability; D011485:Protein Binding; D012016:Reference Values; D012680:Sensitivity and Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019098:Telomerase / Q000276:immunology / Q000494:pharmacology*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D000939:Epitopes; D006680:HLA Antigens; D019098:Telomerase