A wild-type sequence p53 peptide presented by HLA-A24 induces cytotoxic T lymphocytes that recognize squamous cell carcinomas of the head and neck.
A wild-type sequence p53 peptide presented by HLA-A24 induces cytotoxic T lymphocytes that recognize squamous cell carcinomas of the head and neck.
复制标题
DOI：
--
复制
发表时间：
2000-03
期刊：
影响因子：
--
通讯作者：
M. Eura;K. Chikamatsu;F. Katsura;A. Obata;Y. Sobao;M. Takiguchi;Yongsheng Song;E. Appella;T. Whiteside;A. Deleo
中科院分区：
文献类型：
--
作者：
M. Eura;K. Chikamatsu;F. Katsura;A. Obata;Y. Sobao;M. Takiguchi;Yongsheng Song;E. Appella;T. Whiteside;A. Deleo
已经积累的证据表明，对人野生型序列p53表位特异的HLA-A2限制性CTL裂解表达突变型p53的肿瘤细胞。为了探索野生型序列p53肽也可用于表达HLA-A24抗原（另一种常见的HLA I类等位基因）的患者的疫苗的可能性，我们研究了从正常供体的外周血淋巴细胞诱导HLA-A24限制性p53特异性CTL。在六种具有HLA-A24结合基序的p53衍生肽中，发现p53肽125-134（p53（125-134））具有高结合能力，并使用肽脉冲的自体树突状细胞和随后的细胞因子白细胞介素2和白细胞介素7培养，诱导来自外周血单核细胞的肽特异性CTL。大量CTL群体裂解肽脉冲的HLA-A24+靶标以及HLA-A24+头颈部鳞状细胞癌（SCCHN）细胞系。然而，IFN-γ预处理HLA-A24+ SCCHN细胞系对于裂解是必需的，这表明这些CTL需要高于肿瘤细胞正常表达的配体密度来介导裂解。此外，通过有限稀释从大量群体分离的命名为TH#99的克隆CTL比大量CTL群体更有效地裂解HLA-A24+ SCCHN靶。抗HLA-DR单克隆抗体对细胞溶解无明显抑制作用，而抗HLA-I单克隆抗体对细胞溶解有明显抑制作用。这些结果表明，识别野生型序列p53（125-134）的HLA-A24限制性CTL可以使用来自正常HLA-A24+供体获得的外周血淋巴细胞中存在的前体的自体树突细胞产生。这一发现表明，针对野生型序列p53表位的疫苗策略可以扩展到更广泛的癌症患者。
Evidence has accumulated indicating that HLA-A2-restricted CTLs specific for human wild-type sequence p53 epitopes lyse tumor cells expressing mutant p53. To explore the possibility that wild-type sequence p53 peptides could also be used in vaccines for patients expressing HLA-A24 antigen, another frequent HLA class I allele, we investigated the induction of HLA-A24-restricted p53-specific CTLs from the peripheral blood lymphocytes of normal donors. Of six p53-derived peptides possessing an HLA-A24 binding motif, the p53 peptide 125-134 (p53(125-134)) was found to have a high binding capacity and induced peptide-specific CTLs from peripheral blood mononuclear cells, using peptide-pulsed autologous dendritic cells and subsequent cultivation with cytokines interleukin 2 and interleukin 7. Bulk CTL populations lysed peptide-pulsed HLA-A24+ targets as well as HLA-A24+ squamous cell carcinoma of the head and neck (SCCHN) cell lines. However, IFN-gamma pretreatment of HLA-A24+ SCCHN cell lines was necessary for lysis, suggesting that a ligand density higher than that normally expressed by tumor cells is required for these CTLs to mediate lysis. Moreover, a cloned CTL, designated TH#99, isolated from the bulk population by limiting dilution, lysed HLA-A24+ SCCHN targets more efficiently than the bulk CTL population. Lysis was inhibited by anti-HLA class I monoclonal antibody but not by anti-HLA-DR monoclonal antibody. These results indicate that HLA-A24-restricted CTLs recognizing the wild-type sequence p53(125-134) can be generated using autologous dendritic cells from precursors present in peripheral blood lymphocytes obtained from normal HLA-A24+ donors. This finding suggests that vaccine strategies targeting wild-type sequence p53 epitopes can be extended to a wider range of cancer patients.