Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors
Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors
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DOI：
10.1096/fj.05-4493com
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发表时间：
2006-04-01
期刊：
影响因子：
4.8
通讯作者：
Griffioen, Arjan W.
中科院分区：
文献类型：
--
作者：
Dirkx, Anita E. M.;Egbrink, Mirjam G. A. oude;Griffioen, Arjan W.
肿瘤逃避免疫，以及几种抗癌疫苗和细胞免疫治疗方法的失败，被认为是由于血管生成介导的参与白细胞-血管壁相互作用的内皮细胞(EC)黏附分子的抑制。我们假设，抑制血管生成将克服这种逃避免疫的现象。我们通过活体显微镜和免疫组织化学的方法对两种小鼠肿瘤模型进行了体内研究。血管生成抑制剂Anginex、Endostatin和Angiostatin，以及化疗药物紫杉醇在体内通过绕过EC无能，即上调肿瘤血管内皮细胞黏附分子，显著刺激白细胞-血管壁相互作用。体外培养的EC在蛋白质和mRNA水平上的研究证实了这一点。新的血管抑制设计多肽Anginex在克服EC无能方面最有效；增强的白细胞-血管相互作用导致肿瘤浸润性白细胞的数量增加。Angix显著抑制肿瘤生长和微血管密度，显著增加CD45细胞数和CD8(+)细胞毒性T淋巴细胞数。目前的结果表明，免疫治疗策略可以通过结合抗血管生成来改进。-Dirkx，A.E.M.，oude Egbrink，M.G.A.，Castermann，K.，van der Schaft，D.W.J.，Thijssen，V.L.J.L.，Dings，R.P.M.，Kwee，L.，Mayo，K.H.，WagStaff，J.，Bouma-ter Steegge，J.C.A.，Griffioen，A.W.抗血管生成疗法可以克服内皮细胞无能，促进白细胞-内皮相互作用和肿瘤中的渗透。
Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immunohistochemistry in two mouse tumor models. Angiogenesis inhibitors anginex, endostatin, and angiostatin, and the chemotherapeutic agent paclitaxel were found to significantly stimulate leukocyte-vessel wall interactions by circumvention of EC anergy in vivo, i.e., by the up-regulation of endothelial adhesion molecules in tumor vessels. This was confirmed by in vitro studies of cultured EC at the protein and mRNA levels. The new angiostatic designer peptide anginex was most potent at overcoming EC anergy; the enhanced leuko cyte-vessel interactions led to an increase in the numbers of tumor infiltrating leukocytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infiltrated leukocytes (CD45), as well as the number of CD8(+) cytotoxic T lymphocytes, was enhanced markedly. The current results suggest that immunotherapy strategies can be improved by combination with anti-angiogenesis. -Dirkx, A. E. M., oude Egbrink, M. G. A., Castermans, K., van der Schaft, D. W. J., Thijssen, V. L. J. L., Dings, R. P. M., Kwee, L., Mayo, K. H., Wagstaff, J., Bouma-ter Steege, J. C. A., Griffioen, A. W. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors.