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Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy
Science Translational Medicine ( IF 17.1 ) Pub Date : 2021-07-28 , DOI: 10.1126/scitranslmed.abc8922
Yi Sun 1 , Wei Chen 1, 2 , Robert J Torphy 1 , Sheng Yao 3 , Gefeng Zhu 3 , Ronggui Lin 1 , Roberta Lugano 4 , Emily N Miller 1 , Yuki Fujiwara 1 , Li Bian 5 , Linghua Zheng 3 , Sudarshan Anand 6 , Fan Gao 7 , Weizhou Zhang 8 , Sarah E Ferrara 9 , Andrew E Goodspeed 9, 10 , Anna Dimberg 4 , Xiao-Jing Wang 5, 11 , Barish H Edil 12 , Carlton C Barnett 1 , Richard D Schulick 1 , Lieping Chen 3 , Yuwen Zhu 1
Affiliation  

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti–programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.



中文翻译:

阻断 CD93 通路使肿瘤脉管系统正常化,以促进药物输送和免疫治疗

实体瘤内不成熟且功能失调的血管网络对免疫治疗构成了重大障碍,因为它产生了低氧的肿瘤微环境,主动限制了免疫细胞的浸润。这种血管功能障碍的分子基础尚不完全清楚。使用基因组规模受体阵列技术,我们在此展示了胰岛素样生长因子结合蛋白 7 (IGFBP7) 与其受体 CD93 相互作用,随后我们证明这种相互作用会导致肿瘤脉管系统异常。CD93 和 IGFBP7 在肿瘤相关内皮细胞中均上调。IGFBP7 通过不同于 Multimerin-2(CD93 的已知配体)的结构域与 CD93 相互作用。在两种小鼠肿瘤模型中,单克隆抗体阻断 CD93/IGFBP7 相互作用促进血管成熟以减少渗漏,从而减少肿瘤缺氧并增加肿瘤灌注。小鼠体内的 CD93 阻断增加了药物输送,从而改善了对吉西他滨或氟尿嘧啶的抗肿瘤反应。CD93 通路的阻断引发肿瘤内效应 T 细胞的大幅增加,从而使小鼠肿瘤对免疫检查点治疗敏感。最后,对接受抗程序性死亡 1/程序性死亡配体 1 治疗的癌症患者样本的分析表明,IGFBP7/CD93 通路的过度表达与治疗反应不佳相关。因此,我们的研究确定了与肿瘤血管功能障碍有关的分子相互作用,并揭示了一种促进治疗干预有利的肿瘤微环境的方法。

更新日期:2021-07-29
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