An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53
An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53
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DOI：
10.1038/sj.gt.3301670
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发表时间：
2002-03-01
期刊：
影响因子：
5.1
通讯作者：
Gabrilovich, DI
中科院分区：
文献类型：
--
作者：
Nikitina, EY;Chada, S;Gabrilovich, DI
基于P53的免疫是一种很有吸引力的肿瘤免疫治疗方法，因为P53蛋白在肿瘤中积聚，而在正常细胞中不积聚。然而，目前尚不清楚在体内是否能产生针对自身蛋白(P53)的免疫反应。用含鼠全长野生型p53基因的重组腺病毒载体转导小鼠树突状细胞(DC)。用这些细胞重复免疫可保护60%的小鼠免受携带p53基因点突变的甲基肉瘤细胞的攻击。通过结扎CD40激活树突状细胞可显著提高免疫效果：所有小鼠均可抵抗甲基肉瘤。用活化的Ad-P53转导的树突状细胞治疗甲基阿司匹林荷瘤小鼠，6只小鼠中有4只表现出完全的肿瘤排斥反应。CTL实验证实了抗肿瘤免疫反应的特异性。对DC的表型和功能的分析表明，CD40结扎对这些细胞的作用因其感染Ad-P53而增强。这些小鼠的中和性抗腺病毒抗体水平中等程度升高。在对治疗小鼠进行详细的病理评估时，没有明显的自身免疫反应迹象。这些数据表明，激活的Ad-P53感染的树突状细胞能够打破对该蛋白的耐受性，并可用于癌症的免疫治疗。
P53-based immunization is an attractive approach to cancer immunotherapy due to the accumulation of p53 protein in tumor, but not in normal cells. However, it was not known whether immune response against self-protein (p53) could be generated in vivo. Mouse dendritic cells (DCs) were transduced with adenoviral construct containing murine full-length wild-type p53 (Ad-p53). Repeated immunizations with these cells protected 60% of mice against challenge with MethA sarcoma cells bearing point mutations in p53 gene. Activation of DCs via ligation of CD40 significantly improved the results of immunization: all mice were protected against MethA sarcoma. The treatment of MethA tumor-bearing mice with activated Ad-p53-transduced DCs showed complete tumor rejection in four out of six mice. The specificity of antitumor immune response was confirmed by CTL assay. The analysis of phenotype and function of DCs demonstrated that the effect of CD40 ligation on these cells was enhanced by their infection with Ad-p53. The level of neutralizing anti-adenovirus antibody was moderately elevated in these mice. No signs of autoimmune reaction were evident during detailed pathological evaluation of treated mice. These data demonstrate that activated Ad-p53-infected DCs are able to break tolerance to this protein and can be used in immunotherapy of cancer.