Activated Local Immunity by CC Chemokine Ligand 19-Transduced Embryonic Endothelial Progenitor Cells Suppresses Metastasis of Murine Ovarian Cancer
Activated Local Immunity by CC Chemokine Ligand 19-Transduced Embryonic Endothelial Progenitor Cells Suppresses Metastasis of Murine Ovarian Cancer
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DOI：
10.1002/stem.256
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发表时间：
2010-01-01
期刊：
影响因子：
5.2
通讯作者：
Konishi, Ikuo
中科院分区：
文献类型：
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作者：
Hamanishi, Junzo;Mandai, Masaki;Konishi, Ikuo
虽然肿瘤微环境在肿瘤免疫治疗的成功中起着关键作用，但由于缺乏合适的靶点系统，局部免疫的有效操作是困难的。众所周知，骨髓来源的内皮祖细胞在肿瘤血管生成过程中被积极招募。利用这一特征，我们试图建立一种新的治疗方式，利用转导免疫激活基因的胚胎内皮祖细胞(EEPC)来靶向多转移的肿瘤血管。逆转录病毒转导小鼠CC趋化因子配体19(CCL19)基因，CCL19是一种淋巴细胞迁移趋化因子。将小鼠卵巢癌细胞系OV2944-HM-1(HM-1)与CCL19转导的eEPC(eEPC-CCL19)一起皮下接种B6C3F1小鼠，获得免疫活性和抑瘤效应。在该模型中，与对照组相比，eEPC-CCL19表现出肿瘤抑制并伴有肿瘤浸润性CD8+淋巴细胞的增加。相反，当同样的实验在免疫缺陷(SCID)小鼠身上进行时，没有观察到肿瘤抑制，这表明T细胞功能在这个系统中起着至关重要的作用。接下来，我们通过尾静脉注射HM-1细胞或B16黑色素瘤细胞建立了肺转移模型。随后静脉注射eEPC-CCL19可减少肺转移的数量，延长生存期。在使用HM-1的腹膜扩散模型中也观察到了抗肿瘤作用。这些结果表明，使用内皮祖细胞系统地传递免疫激活信号可以改变肿瘤的免疫微环境，从而产生治疗效果，这可能为多种恶性肿瘤的多转移靶向提供一种新的策略。干细胞2010；28：164-173
Although tumor microenvironments play a key role in successful tumor immunotherapy, effective manipulation of local immunity is difficult because of the lack of an appropriate target system. It is well known that bone marrow-derived endothelial progenitor cells (EPCs) are actively recruited during tumor angiogenesis. Using this feature, we attempted to establish a novel therapeutic modality that targets tumor vessels of multiple metastases using embryonic endothelial progenitor cells (eEPCs) transduced with an immune-activating gene. The eEPCs were retrovirally transduced with the mouse CC chemokine ligand 19 (CCL19) gene, a lymphocyte-migrating chemokine. The mouse ovarian cancer cell line OV2944-HM-1 (HM-1) was inoculated subcutaneously into B6C3F1 mice, along with CCL19-tranduced eEPCs (eEPC-CCL19), resulting in immunologic activity and tumor-inhibitory effects. In this model, eEPC-CCL19 showed tumor repression accompanied by increased tumor-infiltrating CD8+ lymphocytes compared with the control group. In contrast, no tumor repression was observed when the same experiment was done in immunodeficient (SCID) mice, suggesting a crucial role of T-cell function in this system. Next, we established a lung metastasis model by injecting HM-1 cells or B16 melanoma cells via the tail vein. Subsequent intravenous injection of eEPC-CCL19 leads to a decrease in the number of lung metastasis and prolonged survival. Antitumor effects were also observed in a peritoneal dissemination model using HM-1. These results suggest that systemic delivery of an immune-activating signal using EPCs can alter the tumor immune microenvironment and lead to a therapeutic effect, which may provide a novel strategy for targeting multiple metastases of various malignancies. STEM CELLS 2010; 28: 164-173