Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma
Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma
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DOI：
10.1002/hep.21203
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发表时间：
2006-06-01
期刊：
影响因子：
13.5
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
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作者：
Mizukoshi, Eishiro;Nakamoto, Yasunari;Kaneko, Shuichi
人类端粒酶逆转录酶，hTERT，已被确定为端粒延长所需的催化酶。HTERT在大多数肿瘤细胞中表达，但在大多数成人细胞中很少表达。有报道称，80%~90%的肝细胞癌表达hTERT，这使该酶成为肝细胞癌免疫治疗的潜在靶点。在目前的研究中，我们确定了hTERT衍生的、人类白细胞抗原A*2402限制性的细胞毒性T细胞(CTL)表位，并分析了肝细胞癌患者中hTERT特异性的CTL反应。在主要组织相容性复合体结合实验中，含有该表位的多肽与人类白细胞抗原-A*2402具有较高的亲和力，并能在hTERT基因免疫的人类白细胞抗原-A*2402/K-b转基因小鼠和肝癌患者体内诱导hTERT特异性CTL。CTL能够依赖hTERT的表达水平以一种HLA-A*2402限制性的方式杀伤肝癌细胞系，并且无论肝炎病毒感染与否，CTL都能被诱导。ELISPOT法检测到单个hTERT表位特异性T细胞数为10~100个/3×10(5)PBMCs，阳性T细胞反应率为6.9%~12.5%。即使在早期肝细胞癌患者中也能观察到hTERT特异性T细胞应答，肝细胞癌患者肿瘤组织中hTERT/四聚体(+)CD8(+)T细胞的频率很高，且具有功能性。总之，这些结果表明hTERT是基于T细胞的肝癌免疫治疗的一个有吸引力的靶点，所识别的hTERT表位可能对免疫治疗和分析宿主对肝癌的免疫反应都有价值。
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/K-b 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.