Tumor mRNA-loaded dendritic cells elicit tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma
Tumor mRNA-loaded dendritic cells elicit tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma
复制标题
DOI：
10.1007/s00262-003-0408-5
复制
发表时间：
2003-10-01
影响因子：
5.8
通讯作者：
Tanaka, R
中科院分区：
文献类型：
--
作者：
Kobayashi, T;Yamanaka, R;Tanaka, R
在这项研究中，我们证明了肿瘤mRNA负载的树突状细胞可以在恶性胶质瘤患者中诱导针对自体肿瘤细胞的特异性CD8(+)细胞毒性T淋巴细胞(CTL)反应。3例患者的CTL对自体胶质瘤细胞有较强的杀伤活性，对自体淋巴母细胞和EBV转化的细胞株无杀伤作用，对NK敏感细胞株K-562有不同程度的杀伤作用。此外，树突状细胞致敏的正常大脑mRNA未能诱导对自体胶质瘤细胞的杀伤活性，这表明缺乏自身免疫反应。两名患者的CD8(+)T细胞对自体胶质瘤细胞表现出适度的细胞毒作用。通过酶联免疫吸附试验检测，在这些无效启动期间分离的CD8(+)T细胞分泌大量的IL-10和少量的干扰素-γ。CD8(+)T细胞反应中的2型偏向是这些患者缺乏细胞毒效应功能的原因。抗HLAI类抗体对自体胶质瘤细胞的杀伤作用可被显著抑制。这些结果表明，肿瘤基因负载的DC可以作为一种有效的工具，在体外诱导胶质瘤特异性CD8(+)CTL杀伤自体胶质瘤细胞。然而，一些患者对肿瘤特异性的高耐受性可能是治疗性疫苗接种的一个重要障碍。这些结果可能对恶性胶质瘤患者的免疫治疗有重要意义。转染肿瘤总RNA的DC可能是一种诱导针对全部胶质瘤抗原的免疫反应的方法。
In this study, we demonstrate that tumor mRNA-loaded dendritic cells can elicit a specific CD8(+) cytotoxic T-lymphocyte (CTL) response against autologous tumor cells in patients with malignant glioma. CTLs from three patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts or EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Also, DCs-pulsed normal brain mRNA failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two patients' CD8(+) T cells expressed a modest cytotoxicity against autologous glioma cells. CD8(+) T cells isolated during these ineffective primings secreted large amounts of IL-10 and smaller amounts of IFN-gamma as detected by ELISA. Type 2 bias in the CD8(+) T-cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor mRNA-loaded DC can be an effective tool in inducing glioma-specific CD8(+) CTLs able to kill autologous glioma cells in vitro. However, high levels of tumor-specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs transfected with total tumor RNA may represent a method for inducing immune responses against the entire repertoire of glioma antigens.