Niethammer Andreas G, Xiang Rong, Becker Jürgen C, Wodrich Harald, Pertl Ursula, Karsten Gabriele, Eliceiri Brian P, Reisfeld Ralph A
Department of Immunology, Scripps Research Institute, La Jolla, California, USA.
Nat Med. 2002 Dec;8(12):1369-75. doi: 10.1038/nm1202-794. Epub 2002 Nov 4.
Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.
由于肿瘤细胞的异质性和基因不稳定性，它们是免疫治疗难以捉摸的靶点。在此，我们描述了一种新型口服DNA疫苗，其靶向肿瘤脉管系统中稳定增殖的内皮细胞而非肿瘤细胞。靶向作用通过肿瘤脉管系统中增殖内皮细胞上调的血管内皮生长因子受体2（FLK-1）实现。该疫苗有效保护小鼠免受黑色素瘤、结肠癌和肺癌细胞的致死性攻击，并在治疗环境中减少已形成转移灶的生长。CTL介导的内皮细胞杀伤表明针对这种自身抗原的外周免疫耐受被打破，导致自发性和实验性肺转移的扩散显著减少。肿瘤脉管系统中的血管生成受到抑制，而生育能力、神经肌肉功能或造血功能未受损害，尽管伤口愈合略有延迟。我们的策略规避了靶向基因不稳定肿瘤细胞的问题。这种方法可能为癌症治疗的合理设计提供一种新策略。
