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000180035 0247_ $$2doi$$a10.1016/j.medj.2021.10.002
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000180035 1001_ $$aO'Connor, Marie N$$b0
000180035 245__ $$aLRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.
000180035 260__ $$aAmsterdam$$bElsevier$$c2021
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000180035 520__ $$aA poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility.Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated.In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active.LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366).
000180035 536__ $$0G:(DE-HGF)POF4-311$$a311 - Zellbiologie und Tumorbiologie (POF4-311)$$cPOF4-311$$fPOF IV$$x0
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000180035 650_7 $$2Other$$aCAR-T cell
000180035 650_7 $$2Other$$aPre-clinical research
000180035 650_7 $$2Other$$acancer therapy
000180035 650_7 $$2Other$$aendothelial cell
000180035 650_7 $$2Other$$aimmunotherapy
000180035 650_7 $$2Other$$aleucine-rich α-2-glycoprotein 1
000180035 650_7 $$2Other$$apericyte
000180035 650_7 $$2Other$$atransforming growth factor β
000180035 650_7 $$2Other$$atumor microenvironment
000180035 650_7 $$2Other$$avascular normalization
000180035 650_7 $$2Other$$avasculopathic
000180035 650_7 $$2NLM Chemicals$$aGlycoproteins
000180035 650_7 $$2NLM Chemicals$$aLRG1 protein, mouse
000180035 650_2 $$2MeSH$$aAnimals
000180035 650_2 $$2MeSH$$aEndothelial Cells: metabolism
000180035 650_2 $$2MeSH$$aGlycoproteins: genetics
000180035 650_2 $$2MeSH$$aImmunotherapy
000180035 650_2 $$2MeSH$$aMice
000180035 650_2 $$2MeSH$$aNeoplasms: therapy
000180035 650_2 $$2MeSH$$aNeovascularization, Pathologic: genetics
000180035 650_2 $$2MeSH$$aTumor Microenvironment
000180035 7001_ $$aKallenberg, David M$$b1
000180035 7001_ $$aCamilli, Carlotta$$b2
000180035 7001_ $$aPilotti, Camilla$$b3
000180035 7001_ $$aDritsoula, Athina$$b4
000180035 7001_ $$0P:(DE-He78)5da14633266cbfff7746cf529c110673$$aJackstadt, Rene-Filip$$b5$$udkfz
000180035 7001_ $$aBowers, Chantelle E$$b6
000180035 7001_ $$aWatson, H Angharad$$b7
000180035 7001_ $$aAlatsatianos, Markella$$b8
000180035 7001_ $$aOhme, Julia$$b9
000180035 7001_ $$aDowsett, Laura$$b10
000180035 7001_ $$aGeorge, Jestin$$b11
000180035 7001_ $$aBlackburn, Jack W D$$b12
000180035 7001_ $$aWang, Xiaomeng$$b13
000180035 7001_ $$0P:(DE-He78)1956b17ee4a34a5fdd72287aca7cdc0a$$aSinghal, Mahak$$b14
000180035 7001_ $$0P:(DE-He78)2e92d0ae281932fc7347d819fec36b0b$$aAugustin, Hellmut G$$b15
000180035 7001_ $$aAger, Ann$$b16
000180035 7001_ $$aSansom, Owen J$$b17
000180035 7001_ $$aMoss, Stephen E$$b18
000180035 7001_ $$aGreenwood, John$$b19
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