Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.
Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.
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DOI：
10.1038/sj.bjc.6604965
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发表时间：
2009-04-07
影响因子：
8.8
通讯作者：
Perez-Gracia, J. L.
中科院分区：
文献类型：
--
作者：
Alfaro, C.;Suarez, N.;Gonzalez, A.;Solano, S.;Erro, L.;Dubrot, J.;Palazon, A.;Hervas-Stubbs, S.;Gurpide, A.;Lopez-Picazo, J. M.;Grande-Pulido, E.;Melero, I.;Perez-Gracia, J. L.
血管内皮生长因子（VEGF）抑制树突状细胞（DC）的分化和成熟，表明这种促血管生成因子具有潜在的免疫抑制作用。贝伐单抗、索拉非尼和舒尼替尼靶向vegf介导的血管生成，并对几种类型的癌症有活性，但它们对免疫系统的影响尚不清楚。本研究发现，缺氧培养的肾癌细胞系的VEGF和上清液可以改变人单核细胞向DC的分化。通过同种异体混合t淋巴细胞反应来评估，DC的活性受损。贝伐单抗和索拉非尼，而不是舒尼替尼，逆转了VEGF的抑制作用，但对肿瘤上清介导的抑制作用无效。在VEGF影响下成熟的树突状细胞表达较少的人白细胞抗原dr （HLA-DR）和CD86，贝伐单抗和索拉非尼可以恢复这种作用。最后，肿瘤细胞上清液通过成熟的DC降低了白细胞介素-12 （IL-12）的产生，并且这种抑制作用没有被任何测试药物恢复，无论是单独给药还是联合给药。肿瘤细胞上清液的有害作用主要由不同于VEGF的热稳定性分子介导。这些结果表明，抑制单核细胞向DC分化是一个多因子效应，它们支持血管生成抑制剂与免疫调节剂联合使用的发展。
Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.
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