Vascular dysfunction contributes to the pro-oncogenic tumor microenvironment and impedes the delivery of therapeutics. Normalizing of the tumor vasculature has therefore become a potential therapeutic objective. We previously reported that the secreted glycoprotein, leucine-rich α-2-glycoprotein 1 (LRG1), contributes to the formation of pathogenic neovascularization. Here we show that in mouse models of cancer, Lrg1 is induced in tumor endothelial cells. We demonstrate that the expression of LRG1 impacts on tumor progression as Lrg1 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 significantly 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 (cold) to immune active (hot). LRG1 therefore drives vascular abnormalization and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.

中文翻译：

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LRG1使肿瘤血管不稳定并限制免疫疗法的效力

血管功能障碍促成促癌性肿瘤微环境并阻碍治疗剂的递送。因此，肿瘤脉管系统的正常化已成为潜在的治疗目标。我们以前曾报道过，分泌的糖蛋白，富含亮氨酸的α-2-糖蛋白1（LRG1）有助于病原性新血管形成。在这里，我们显示在癌症的小鼠模型中，Lrg1在肿瘤内皮细胞中被诱导。我们证明LRG1的表达对肿瘤的进展有影响，因为Lrg1缺失或用LRG1功能阻断抗体进行治疗可抑制肿瘤生长并提高生存率。抑制LRG1可增加内皮细胞周细胞覆盖率并改善血管功能，从而显着提高顺铂化疗的疗效，过继T细胞疗法和免疫检查点抑制（anti-PD1）疗法。通过免疫疗法，LRG1抑制导致肿瘤微环境从主要是免疫沉默（冷）转变为免疫活性（热）的重大转变。因此，LRG1驱动血管异常，其抑制作用代表了一种新型且有效的手段，可提高癌症治疗剂的功效。