Vascular Biology Program and Department of Surgery, Childrens' Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
FASEB J. 2010 May;24(5):1411-8. doi: 10.1096/fj.09-147025. Epub 2009 Dec 14.
Dendritic cells (DCs)--immunomodulatory cells that initiate adaptive immune responses--have recently been shown to exert proangiogenic effects when infiltrating the tumor microenvironment. As tumors that escape immune surveillance inhibit DC maturation, we explored whether maturation status determines their ability to promote angiogenesis and whether angiogenesis depends on the presence of DCs. Using mouse xenograft models of human tumors, we show that fast-growing "angiogenic" tumors are infiltrated by a more immature DC population than respective dormant avascular tumors. Accordingly, supplementation of immature DCs, but not mature DCs, enhanced tumor growth. When DCs were mixed with Matrigel and injected subcutaneously into mice, only immature DCs promoted the ingrowth of patent blood vessels. Notably, depletion of DCs in a transgenic mouse model that allows for their conditional ablation completely abrogated basic fibroblast growth factor-induced angiogenesis in Matrigel plugs, and significantly inhibited tumor growth in these mice. Because immature DCs actively promote angiogenesis and tumor growth, whereas DC maturation or ablation suppresses this response, we conclude that angiogenesis is dependent on the presence of immature DCs. Thus, cancer immunotherapies that promote DC maturation may act by both augmenting the host immune response to the tumor and by suppressing tumor angiogenesis.
树突状细胞 (DCs)——启动适应性免疫反应的免疫调节细胞——最近被证明在浸润肿瘤微环境时具有促血管生成作用。由于逃避免疫监视的肿瘤会抑制 DC 成熟，因此我们探讨了成熟状态是否决定其促进血管生成的能力，以及血管生成是否依赖于 DC 的存在。我们使用人肿瘤的小鼠异种移植模型表明，与相应的休眠无血管肿瘤相比，快速生长的“血管生成”肿瘤中浸润的 DC 群体更不成熟。因此，补充不成熟的 DC 而不是成熟的 DC 会增强肿瘤生长。当将 DC 与 Matrigel 混合并注入小鼠皮下时，只有不成熟的 DC 促进了有功能的血管的生长。值得注意的是，在允许条件性消融的转基因小鼠模型中耗尽 DC 可完全阻断碱性成纤维细胞生长因子诱导的 Matrigel 塞中的血管生成，并显著抑制这些小鼠中的肿瘤生长。由于不成熟的 DC 积极促进血管生成和肿瘤生长，而 DC 成熟或消融会抑制这种反应，因此我们得出结论，血管生成依赖于不成熟的 DC 的存在。因此，促进 DC 成熟的癌症免疫疗法可能通过增强宿主对肿瘤的免疫反应和抑制肿瘤血管生成来发挥作用。
