Institute of Ophthalmology, University College London, London SE5 8BN, UK.
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
Med. 2021 Nov 12;2(11):1231-1252.e10. doi: 10.1016/j.medj.2021.10.002. Epub 2021 Nov 3.
A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility.
Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated.
In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active.
LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.
Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366).
功能失调的肿瘤血管是致癌的，并可能阻碍治疗药物的输送。因此，使血管正常化可能是有益的。我们之前报道过，分泌糖蛋白富含亮氨酸的 α-2-糖蛋白 1（LRG1）有助于病理性新生血管形成。在这里，我们研究肿瘤中的 LRG1 是否是血管病变的，并研究其抑制作用是否具有治疗效用。
在野生型和 Lrg1 敲除小鼠的皮下和基因工程小鼠模型中分析肿瘤生长和血管结构。研究 LRG1 抗体阻断作为单一疗法或与联合疗法一起对血管功能、肿瘤生长和浸润淋巴细胞的影响。
在癌症的小鼠模型中，LRG1 在肿瘤内皮细胞中表达，与人类癌症中蛋白表达增加一致。LRG1 的表达影响肿瘤进展，因为 Lrg1 基因缺失或用 LRG1 功能阻断抗体治疗可抑制肿瘤生长并提高存活率。抑制 LRG1 增加了内皮细胞周细胞覆盖并改善了血管功能，从而增强了顺铂化疗、过继性 T 细胞治疗和免疫检查点抑制（抗 PD1）治疗的疗效。在免疫治疗中，LRG1 抑制导致肿瘤微环境从主要免疫沉默转变为免疫活跃。
LRG1 驱动血管异常化，其抑制代表了改善癌症治疗疗效的一种新的有效方法。
惠康信托基金（206413/B/17/Z），英国研究与创新署/医学研究理事会（G1000466、MR/N006410/1、MC/PC/14118 和 MR/L008742/1），英国心脏基金会（PG/16/50/32182），威尔士健康与护理研究（CA05），英国癌症研究基金会（C42412/A24416 和 A17196），欧洲研究理事会（ColonCan 311301 和 AngioMature 787181）和德国研究基金会（CRC1366）。
