持续的血管生成使肿瘤内皮细胞对炎症因子不敏感，并干扰白细胞的粘附，导致免疫逃逸。这个过程称为肿瘤内皮细胞无反应性。我们旨在研究抗血管生成药物是否能克服内皮细胞无反应性并提供促炎性条件。对VEGF信号通路靶向药物治疗的肾癌(RCC)患者组织和对照组组织进行了RNAseq和免疫组化分析。分析培养内皮细胞、早期临床模型和人体组织中的粘附分子调节，并与白细胞浸润相关。结果表明，sunitinib或bevacizumab药物治疗克服了肿瘤内皮细胞无反应性。这种治疗导致肿瘤增强了炎症状态，表现为各种主要白细胞亚群的增强浸润，包括T细胞、调节性T细胞、M1和M2样型的巨噬细胞和激活的树突状细胞。在体外，将血管生成内皮细胞暴露于抗血管生成药物可使ICAM-1表达恢复正常。此外，一组酪氨酸激酶抑制剂能增加非黏附和单核细胞白细胞的经内皮迁移。肾癌患者的原发性肿瘤中，ICAM-1表达量在Sunitinib组和bevacizumab组均得到显著提高。基因组分析证实，VEGF靶向治疗后，免疫细胞浸润和ICAM-1表达之间存在相关性。结果支持抗血管生成疗法可增强免疫反应的新兴概念，并展示了免疫疗法方法如何可以从与抗血管生成化合物的联合中受益。 © 2022作者。

Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions.Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration.It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment.The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds.© 2022. The Author(s).