Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: Identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy
Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: Identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy
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DOI：
10.4049/jimmunol.178.3.1505
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Feron, Olivier
中科院分区：
文献类型：
--
作者：
Bouzin, Caroline;Brouet, Agnes;Feron, Olivier
肿瘤可以在多个水平逃避免疫应答，包括通过淋巴细胞-血管壁相互作用中的缺陷。肿瘤血管内皮细胞（EC）的血管生成特性可能是这种无反应性的原因。在这项研究中，我们研究了除下调粘附分子外，是否还涉及其他机制，特别是依赖于小窝平台的信号通路。为了模拟肿瘤微环境的影响，将EC暴露于TNF-α和促血管生成的血管内皮生长因子（VEGF）。我们确定了一个显着的抑制淋巴细胞粘附激活EC后，无论是短或长的VEGF预处理。我们进一步证实VEGF并不影响主要粘附分子的丰度，但与EC表面ICAM-1和VCAM-1聚集缺陷相关。我们还发现，过度表达的小窝结构蛋白，小窝蛋白-1，克服了VEGF介导的抑制粘附和恢复ICAM-1集群。相反，EC转导小窝蛋白-1小干扰RNA减少了TNF-α依赖的粘附增加。最后，我们确定了。VEGF诱导的内皮NO合成酶的NO产生是小窝蛋白-1丰度变化的主要靶点。我们发现，NO合成酶抑制剂N-硝基-L-精氨酸甲酯可以逆转VEGF对淋巴细胞粘附和EC细胞骨架重排的抑制作用。对称地，NO供体被证明可以防止ICAM聚集介导的淋巴细胞粘附，从而重现VEGF的作用。总之。这项研究为导致肿瘤EC与免疫细胞无反应性的机制提供了新的见解，并为使用抗血管生成策略作为癌症免疫治疗的辅助方法开辟了新的视角。
Tumors may evade immune responses at multiple levels, including through a defect in the lymphocyte-vessel wall interactions. The angiogenic nature of endothelial cells (EC) lining tumor blood vessels may account for such anergy. In this study, we examined whether mechanisms other than down-regulation of adhesion molecules could be involved, particularly signaling pathways dependent on the caveolae platforms. To mimic the influence of the tumor microenvironment, EC were exposed to TNF-alpha and the proangiogenic vascular endothelial growth factor (VEGF). We identified a dramatic inhibition of lymphocyte adhesion on activated EC following either short or long VEGF pretreatments. We further documented that VEGF did not influence the abundance of major adhesion molecules, but was associated with a defect in ICAM-1 and VCAM-I clustering at the EC surface. We also found that overexpression of the caveolar structural protein, caveolin-1, overcame the VEGF-mediated inhibition of adhesion and restored ICAM-1 clustering. Conversely, EC transduction with a caveolin-1 small interfering RNA reduced the TNF-alpha-dependent increase in adhesion. Finally, we identified. VEGF-induced NO production by the endothelial NO synthase as the main target of the changes in caveolin-1 abundance. We found that the NO synthase inhibitor N-nitro-L-arginine methyl ester could reverse the inhibitory effects of VEGF on lymphocyte adhesion and EC cytoskeleton rearrangement. Symmetrically, a NO donor was shown to prevent the ICAM clustering-mediated lymphocyte adhesion, thereby recapitulating the effects of VEGF. In conclusion. this study provides new insights on the mechanisms leading to the tumor EC anergy vs immune cells and opens new perspectives for the use of antiangiogenic strategies as adjuvant approaches to cancer immunotherapy.