Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.

译文

野生型 (WT) 序列p53肽是广泛适用的癌症疫苗的有吸引力的候选者。这项研究的目的是评估WT p53-based免疫治疗方法对肝细胞癌 (HCC) 患者的潜力。通过在24例HCC患者中使用肽/HLA-A2.1四聚体,在外周血中直接鉴定了对WT p53(149-157) 和WT p53(264-272) hla-a * 0201限制性表位特异性的循环CD8 + T细胞。使用定量实时聚合酶链反应测定法,通过分析颗粒酶B和干扰素-γ mRNA转录来评估WT p53肽特异性刺激后的细胞毒性T淋巴细胞 (CTL) 活性。进行肿瘤免疫表型分析以评估新鲜分离的肿瘤细胞中的p53状态,主要组织相容性复合物 (MHC) 和共刺激分子的表达。与健康对照组相比,HCC患者表现出明显更高的WT p53-specific记忆CD8 + T细胞频率和更强的WT p53-specific CTL活性。p53-specific CD8 + T细胞的频率增加及其活性与肿瘤细胞的选择性HLA-A2等位基因丢失和共刺激分子表达降低相关。此外,p53-specific T细胞数量的增加与肿瘤细胞中高MHC II类表达相吻合,但与肿瘤淋巴结转移分期系统的T状态成反比。我们的结果表明存在自然免疫监视和肿瘤免疫逃避,涉及HCC患者针对WT p53肿瘤抗原的T细胞反应。这些发现可能对癌症疫苗的未来发展具有重要意义。

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