Sustained and NK/CD4+ T Cell-Dependent Efficient Prevention of Lung Metastasis Induced by Dendritic Cells Harboring Recombinant Sendai Virus
Sustained and NK/CD4+ T Cell-Dependent Efficient Prevention of Lung Metastasis Induced by Dendritic Cells Harboring Recombinant Sendai Virus
复制标题
DOI：
10.4049/jimmunol.0803845
复制
发表时间：
2009-10-01
影响因子：
4.4
通讯作者：
Yonemitsu, Yoshikazu
中科院分区：
文献类型：
--
作者：
Komaru, Atsushi;Ueda, Yasuji;Yonemitsu, Yoshikazu
最近，我们证明了有效的抗肿瘤免疫小鼠肿瘤使用重组仙台病毒（rSeVs）激活的树突状细胞（DC），并提出了一个新的概念，“免疫刺激病毒疗法，”癌症免疫治疗。然而，关于这种方法在预防转移性疾病中的功效的信息很少。在这项研究中，我们研究了免疫接种DCs激活的融合基因缺失的非传染性rSeV（rSeV/dF）使用小鼠肺转移模型的疗效。在肿瘤接种前2天，团注和静脉内给予携带rSeV/dF-GFP表达的DC而不脉动肿瘤Ag（DC-rSeV/dF-GFP），显示出对c1300神经母细胞瘤肺转移的有效预防，但对RM-9前列腺癌没有。我们发现DC治疗的时机对于抑制RM-9的肺转移是关键的，并且在肿瘤接种前28天看到DC的最佳效果。有趣的是，抗转移作用持续超过3个月，即使当施用的DC已经从肺和与免疫系统相关的器官中清除时。尽管NK细胞活性在肿瘤接种时已经下降至基线水平，但Ab介导的耗竭研究表明，CD 4（+）细胞以及NK细胞的存在（而非活化）对预防肺转移至关重要。这些结果首次证明了通过持续和NK/CD 4（+）细胞依赖性的病毒活化的DC的推注施用有效抑制肺转移，并且可能提示基于DC的免疫治疗晚期恶性肿瘤的潜在新机制。免疫学杂志，2009，183：4211-4219.
We recently demonstrated efficient antitumor immunity against murine tumors using dendritic cells (DCs) activated by recombinant Sendai viruses (rSeVs), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacy of this method in preventing metastatic diseases. In this study, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV (rSeV/dF) using a murine model of lung metastasis. Bolus and i.v. administration of DCs harboring rSeV/dF-expressing GFP without pulsation of tumor Ag (DC-rSeV/dF-GFP) 2 days before tumor inoculation showed efficient prevention against lung metastasis of c1300 neuroblastoma, but not of RM-9 prostatic cancer. We found that the timing of DC therapy was critical for the inhibition of pulmonary metastasis of RM-9, and that the optimal effect of DCs was seen 28 days before tumor inoculation. Interestingly, the antimetastatic effect was sustained for over 3 mo, even when administered DCs were already cleared from the lung and organs related to the immune system. Although NK cell activity had already declined to baseline at the time of tumor inoculation, Ab-mediated depletion studies revealed that CD4(+) cells as well as the presence of, but not the activation of, NK cells were crucial to the prevention of lung metastasis. These results are the first demonstration of efficient inhibition of lung metastasis via bolus administration of virally activated DCs that was sustained and NK/CD4(+) cell-dependent, and may suggest a potentially new mechanism of DC-based immunotherapy for advanced malignancies. The Journal of Immunology, 2009, 183: 4211-4219.