Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Patrycja Nowak-Sliwinska, Judy R. van Beijnum, Christian J. Griffioen, Zowi R. Huinen, Nadine Grima Sopesens, Ralph Schulz, Samir V. Jenkins, Ruud P. M. Dings, Floris H. Groenendijk, Elisabeth J. M. Huijbers, Victor L. J. L. Thijssen, Eric Jonasch, Florry A. Vyth-Dreese, Ekaterina S. Jordanova, Axel Bex, René Bernards, Tanja D. de Gruijl, Arjan W. Griffioen
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引用次数: 9

Abstract

Purpose

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.

Experimental design

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.

Results

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.

Conclusion

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.

Abstract Image

Abstract Image

Abstract Image

VEGF靶向治疗通过逆转肿瘤内皮细胞无能的促炎活性
目的持续的血管生成使肿瘤内皮对炎性细胞因子无反应,并干扰白细胞的粘附,导致免疫逃逸。这个过程被称为肿瘤内皮细胞无能。我们的目的是研究抗血管生成剂是否可以克服内皮细胞的无能并提供促炎条件。实验设计对VEGF通路靶向药物治疗的肾细胞癌(RCC)患者组织和对照组织进行RNAseq和白细胞浸润的免疫组织化学分析。对培养的内皮细胞、临床前模型和人体组织中的粘附分子调节进行了分析,并与白细胞浸润相关。结果舒尼替尼或贝伐单抗治疗肾细胞癌可克服肿瘤内皮细胞无能。这种治疗导致肿瘤的炎症状态增强,其特征是所有主要白细胞亚群的浸润增强,包括T细胞、调节性T细胞、M1和M2样表型的巨噬细胞以及活化的树突状细胞。在体外,血管生成内皮细胞暴露于抗血管生成药物使ICAM-1表达正常化。此外,一组酪氨酸激酶抑制剂显示可增加非粘附性和单核细胞白细胞的跨内皮迁移。在RCC患者的原发性肿瘤中,发现舒尼替尼和贝伐单抗治疗组的ICAM-1表达均显著增加。基因组分析证实了VEGF靶向治疗后免疫细胞浸润增加与ICAM-1表达之间的相关性。结论该结果支持了抗血管生成治疗可以提高免疫力的新概念,并表明了免疫疗法如何从与抗血管生成化合物的组合中获益。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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