Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells.
Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells.
复制标题
使用慢病毒载体工程干细胞治疗小鼠肺转移性肿瘤。
DOI：
10.1038/sj.cgt.7701108
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发表时间：
2008
影响因子：
6.4
通讯作者：
Cui,Y
中科院分区：
文献类型：
--
作者：
Zhang,X;Zhao,P;Kennedy,C;Chen,K;Wiegand,J;Washington,G;Marrero,L;Cui,Y
主动癌症免疫治疗依赖于功能性肿瘤特异性效应T淋巴细胞来消除肿瘤。树突状细胞作为最有效的抗原提呈细胞，已广泛应用于临床和实验肿瘤治疗。我们之前已经证明，慢病毒载体介导的转基因传递到DC祖细胞，包括骨髓细胞和造血干细胞，然后移植支持大量肿瘤抗原呈递DC的系统生成。这些dc随后刺激显著的和全身的免疫激活。在这里，我们研究了这种水平的免疫激活是否足以克服肿瘤诱导的耐受性环境来治疗已建立的侵袭性上皮肿瘤。我们发现粒细胞巨噬集落刺激因子和含有胞嘧啶-磷酸-鸟嘌呤的寡核苷酸联合处理可刺激转基因干细胞原位产生大量肿瘤抗原呈递dc。此外，这些原位生成和激活的dc通过增加抗原特异性CD4和CD8 T细胞的数量和功能，显着刺激了它们的活化，即使在肿瘤耐受环境中也是如此。这使得已建立的肺转移的治疗效果显著改善。本研究提示慢病毒载体修饰的干细胞作为DC祖细胞可作为治疗转移性上皮肿瘤的有效治疗方案。
Active cancer immunotherapy relies on functional tumor-specific effector T lymphocytes for tumor elimination. Dendritic cells (DCs), as most potent antigen-presenting cells, have been popularly employed in clinical and experimental tumor treatments. We have previously demonstrated that lentiviral vector-mediated transgene delivery to DC progenitors, including bone marrow cells and hematopoietic stem cells, followed by transplantation supports systemic generation of great numbers of tumor antigen-presenting DCs. These DCs subsequently stimulate marked and systemic immune activation. Here, we examined whether this level of immune activation is sufficient to overcome tumor-induced tolerogenic environment for treating an established aggressive epithelial tumor. We showed that a combination treatment of granulocyte macrophage-colony stimulating factor and cytosine-phosphate-guanine-containing oligonucleotide stimulated large numbers of tumor antigen-presenting DCs in situ from transgene-modified stem cells. Moreover, these in situ generated and activated DCs markedly stimulated activation of antigen-specific CD4 and CD8 T cells by augmenting their numbers, as well as function, even in a tumor-bearing tolerogenic environment. This leads to significant improvement in the therapeutic efficacy of established pulmonary metastases. This study suggests that lentiviral vector-modified stem cells as DC progenitors may be used as an effective therapeutic regimen for treating metastatic epithelial tumors.