LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.
LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.
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DOI：
10.1016/j.medj.2021.10.002
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发表时间：
2021-11-12
期刊：
影响因子：
--
通讯作者：
Greenwood J
中科院分区：
文献类型：
--
作者：
O'Connor MN;Kallenberg DM;Camilli C;Pilotti C;Dritsoula A;Jackstadt R;Bowers CE;Watson HA;Alatsatianos M;Ohme J;Dowsett L;George J;Blackburn JWD;Wang X;Singhal M;Augustin HG;Ager A;Sansom OJ;Moss SE;Greenwood J
功能不良的肿瘤脉管系统是促癌的，并且可能阻碍治疗剂的递送。因此，使脉管系统正常化可能是有益的。我们先前报道了分泌的糖蛋白富含亮氨酸的a-2-糖蛋白1（LRG1）有助于致病性新生血管形成。在这里，我们研究肿瘤中的LRG1是否是血管性的，以及其抑制是否具有治疗效用。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。研究了LRG1抗体阻断作为单一疗法或与联合疗法组合对血管功能、肿瘤生长和浸润淋巴细胞的影响。在小鼠癌症模型中，Lrg1表达在肿瘤内皮细胞中被诱导，这与人类癌症中蛋白质表达的增加一致。LRG1的表达影响肿瘤进展，因为LRG1基因缺失或用LRG1功能阻断抗体治疗抑制肿瘤生长并改善存活率。LRG1的抑制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。通过免疫疗法，LRG1抑制导致肿瘤微环境从主要免疫沉默到免疫活性的显著转变。LRG1驱动血管异常化，其抑制代表了改善癌症治疗功效的新颖且有效的手段。Wellcome Trust（206413/B/17/Z），UKRI/MRC（G1000466、MR/N006410/1、MC/PC/14118和MR/L008742/1），BHF（PG/16/50/32182）、威尔士健康与护理研究（CA 05）、CRUK（C42412/A24416和A17196）、ERC（ColonCan 311301和AngioMature 787181）和DFG（CRC 1366）。
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 a-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).
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DOI：
10.1038/nri.2017.145
发表时间：
2018-03
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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