Active immunotherapy induces antibody responses that target tumor angiogenesis.
Active immunotherapy induces antibody responses that target tumor angiogenesis.
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DOI：
10.1158/0008-5472.can-10-1852
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Dranoff G
中科院分区：
文献类型：
--
作者：
Schoenfeld J;Jinushi M;Nakazaki Y;Wiener D;Park J;Soiffer R;Neuberg D;Mihm M;Hodi FS;Dranoff G
用抗体或小分子抑制血管内皮生长因子（VEGF）信号传导在多种实体恶性肿瘤中实现临床益处。尽管如此，治疗效果通常不能持续，大多数患者最终死于疾病进展，这表明抗血管生成策略需要额外的优化。用致死性照射的自体肿瘤细胞接种疫苗以分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）和细胞毒性T淋巴细胞相关抗原-4（CTLA-4）的抗体阻断在一些长期响应的受试者中触发肿瘤血管病变。这些反应的特征是肿瘤血管破裂，伴有淋巴细胞和粒细胞浸润以及局部缺血性肿瘤坏死。然而，这种免疫介导的肿瘤血管破坏的机制仍有待澄清。在这里，我们表明，分泌GM-CSF的肿瘤细胞疫苗和CTLA-4阻断引起功能上重要的体液反应，对多种血管生成细胞因子。血管生成素-1和-2的抗体阻断Tie-2结合、下游信号传导、内皮细胞管形成和巨噬细胞趋化性。巨噬细胞抑制因子（MIF）抗体减弱巨噬细胞Tie-2表达和基质金属蛋白酶-9（MMP-9）产生。总之，这些结果描绘了免疫疗法诱导的宿主反应，其广泛靶向肿瘤微环境中的血管生成网络。
The inhibition of vascular endothelial growth factor (VEGF) signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that anti-angiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and -2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy induced host response that broadly targets the angiogenic network in the tumor microenvironment.