TY  - JOUR
AU  - O'Connor, Marie N
AU  - Kallenberg, David M
AU  - Camilli, Carlotta
AU  - Pilotti, Camilla
AU  - Dritsoula, Athina
AU  - Jackstadt, Rene-Filip
AU  - Bowers, Chantelle E
AU  - Watson, H Angharad
AU  - Alatsatianos, Markella
AU  - Ohme, Julia
AU  - Dowsett, Laura
AU  - George, Jestin
AU  - Blackburn, Jack W D
AU  - Wang, Xiaomeng
AU  - Singhal, Mahak
AU  - Augustin, Hellmut G
AU  - Ager, Ann
AU  - Sansom, Owen J
AU  - Moss, Stephen E
AU  - Greenwood, John
TI  - LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.
JO  - Med
VL  - 2
IS  - 11
SN  - 2666-6340
CY  - Amsterdam
PB  - Elsevier
M1  - DKFZ-2022-01052
SP  - 1231 - 1252.e10
PY  - 2021
N1  - DKFZ-ZMBH Alliance
AB  - 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).
KW  - Animals
KW  - Endothelial Cells: metabolism
KW  - Glycoproteins: genetics
KW  - Immunotherapy
KW  - Mice
KW  - Neoplasms: therapy
KW  - Neovascularization, Pathologic: genetics
KW  - Tumor Microenvironment
KW  - CAR-T cell (Other)
KW  - Pre-clinical research (Other)
KW  - cancer therapy (Other)
KW  - endothelial cell (Other)
KW  - immunotherapy (Other)
KW  - leucine-rich α-2-glycoprotein 1 (Other)
KW  - pericyte (Other)
KW  - transforming growth factor β (Other)
KW  - tumor microenvironment (Other)
KW  - vascular normalization (Other)
KW  - vasculopathic (Other)
KW  - Glycoproteins (NLM Chemicals)
KW  - LRG1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35590198
DO  - DOI:10.1016/j.medj.2021.10.002
UR  - https://inrepo02.dkfz.de/record/180035
ER  -