%0 Journal Article
%A Mertlitz, Sarah
%A Riesner, Katarina
%A Kalupa, Martina
%A Uhlig, Nora
%A Cordes, Steffen
%A Verlaat, Lydia
%A Jamali, Mina
%A Li, Ningyu
%A Mohamed, Hadeer Mohamed Elsayed Rasheed
%A Bullinger, Lars
%A Moss, Stephen
%A Greenwood, John
%A Jatzlau, Jerome
%A Knaus, Petra
%A Vallecillo-Garcia, Pedro
%A Penack, Olaf
%T Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy.
%J Journal for ImmunoTherapy of Cancer
%V 13
%N 3
%@ 2051-1426
%C London
%I BioMed Central
%M DKFZ-2025-00593
%P e009372
%D 2025
%X Previous data indicated that the leucine-rich α-2 glycoprotein 1 (LRG1) pathway contributes to vascular dysfunction during cancer growth. Therapeutic targeting of LRG1 normalized tumor vessel dysfunction and enhanced the efficacy of anti-cancer adoptive T cell therapy. A major clinical problem after allogeneic hematopoietic stem cell transplantation (alloHSCT) and after chimeric antigen receptor (CAR) T-cell therapy is the induction of hyperinflammatory side effects, which are typically associated with severe endothelial dysfunction.We investigated LRG1 in preclinical models and in patient samples.In prospective studies, we found elevated LRG1 serum levels in patients with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome after CAR-T-cell therapy as well as in patients with acute graft-versus-host disease (aGVHD) after alloHSCT.In preclinical models of aGVHD, we found vasculature-associated LRG1 upregulation as well as LRG1 pathway gene upregulation. The genetic deletion of LRG1 in alloHSCT donors and in alloHSCT recipients led to reduced clinical and histological aGVHD. In line with this, LRG1 deletion led to clinically and histologically reduced disease severity in experimental inflammatory models of colitis (dextran sulfate sodium colitis) and paw edema. LRG1 deletion reduced inflammation-related vascular leakiness, endothelial cell proliferation, and migration.The current data support the hypothesis that LRG1 is an attractive therapeutic target after alloHSCT and after CAR-T cell therapy for cancer because of its role in dysfunctional tumor vessels as well as in inflammatory complications.
%K Humans
%K Animals
%K Glycoproteins: metabolism
%K Mice
%K Immunotherapy, Adoptive: methods
%K Immunotherapy, Adoptive: adverse effects
%K Graft vs Host Disease: etiology
%K Hematopoietic Stem Cell Transplantation: adverse effects
%K Hematopoietic Stem Cell Transplantation: methods
%K Male
%K Transplantation, Homologous
%K Female
%K Inflammation
%K Middle Aged
%K Cytokine Release Syndrome: etiology
%K Receptors, Chimeric Antigen: metabolism
%K Prospective Studies
%K Cytokine release syndrome (Other)
%K Graft versus host disease - GVHD (Other)
%K Immune related adverse event - irAE (Other)
%K Immunotherapy (Other)
%K Stem cell (Other)
%K LRG1 protein, human (NLM Chemicals)
%K Glycoproteins (NLM Chemicals)
%K LRG1 protein, mouse (NLM Chemicals)
%K Receptors, Chimeric Antigen (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40118496
%R 10.1136/jitc-2024-009372
%U https://inrepo02.dkfz.de/record/300093