Thimme Robert, Neagu Michaela, Boettler Tobias, Neumann-Haefelin Christoph, Kersting Nadine, Geissler Michael, Makowiec Frank, Obermaier Robert, Hopt Ulrich T, Blum Hubert E, Spangenberg Hans Christian
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
Hepatology. 2008 Dec;48(6):1821-33. doi: 10.1002/hep.22535.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with a poor prognosis and limited therapeutic options. Therefore, the development of novel therapeutic strategies is of high priority. alpha-Fetoprotein (AFP) is overexpressed in the majority of HCCs. Priming of immune responses against AFP results in significant protective antitumoral T cell responses in the mouse model. Little information is available about the hierarchy, breadth, frequency, and peripheral versus intrahepatic distribution of AFP-specific CD8(+) T cell responses in patients with HCC. To address these important issues we comprehensively analyzed CD8(+) T cell responses against full-length AFP in peripheral blood, tumor liver tissue, and nontumor liver tissue from patients with HCC using overlapping AFP peptides. The AFP-specific CD8(+) T cell response was also tested in peripheral blood and liver from patients chronically infected with hepatitis C virus (HCV) and compared to the HCV-specific CD8(+) T cell response. The majority of patients with HCC showed AFP-specific responses, with many responses directed against previously unreported epitopes. These responses were primarily detectable in the HCC tissue and mainly targeted the C-terminus of AFP. Interestingly, AFP-specific T cells were not only found in patients with HCC but also in patients with chronic HCV infection, other liver diseases, and less frequently in healthy subjects.
In patients with HCC, a high frequency of AFP-specific CD8(+) T cells directed against different epitopes suggest that AFP has a strong and broad immunogenicity. Further, CD8(+) T cells specific for the self-antigen AFP are present in the normal T cell repertoire and are not centrally or peripherally deleted. Our results provide support for strategies to boost AFP-specific CD8(+) T cell responses in patients with HCC but also demonstrate a diversity of immune responses that may be needed for protection.
肝细胞癌（HCC）是全球第五大常见恶性肿瘤，预后较差且治疗选择有限。因此，开发新的治疗策略至关重要。甲胎蛋白（AFP）在大多数肝癌中过度表达。针对AFP引发免疫反应在小鼠模型中可产生显著的保护性抗肿瘤T细胞反应。关于肝癌患者中AFP特异性CD8(+) T细胞反应的层次结构、广度、频率以及外周与肝内分布的信息较少。为解决这些重要问题，我们使用重叠的AFP肽全面分析了肝癌患者外周血、肿瘤肝组织和非肿瘤肝组织中针对全长AFP的CD8(+) T细胞反应。还在慢性丙型肝炎病毒（HCV）感染患者的外周血和肝脏中检测了AFP特异性CD8(+) T细胞反应，并与HCV特异性CD8(+) T细胞反应进行比较。大多数肝癌患者表现出AFP特异性反应，许多反应针对以前未报道的表位。这些反应主要在肝癌组织中可检测到，且主要靶向AFP的C末端。有趣的是，AFP特异性T细胞不仅在肝癌患者中发现，也在慢性HCV感染患者、其他肝病患者中发现，在健康受试者中发现的频率较低。
在肝癌患者中，针对不同表位的高频率AFP特异性CD8(+) T细胞表明AFP具有强大而广泛的免疫原性。此外，针对自身抗原AFP的CD8(+) T细胞存在于正常T细胞库中，未在中枢或外周被清除。我们的结果为增强肝癌患者AFP特异性CD8(+) T细胞反应的策略提供了支持，但也证明了可能需要多种免疫反应来提供保护。
