TY  - JOUR
AU  - Mertlitz, Sarah
AU  - Riesner, Katarina
AU  - Kalupa, Martina
AU  - Uhlig, Nora
AU  - Cordes, Steffen
AU  - Verlaat, Lydia
AU  - Jamali, Mina
AU  - Li, Ningyu
AU  - Mohamed, Hadeer Mohamed Elsayed Rasheed
AU  - Bullinger, Lars
AU  - Moss, Stephen
AU  - Greenwood, John
AU  - Jatzlau, Jerome
AU  - Knaus, Petra
AU  - Vallecillo-Garcia, Pedro
AU  - Penack, Olaf
TI  - Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy.
JO  - Journal for ImmunoTherapy of Cancer
VL  - 13
IS  - 3
SN  - 2051-1426
CY  - London
PB  - BioMed Central
M1  - DKFZ-2025-00593
SP  - e009372
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Animals
KW  - Glycoproteins: metabolism
KW  - Mice
KW  - Immunotherapy, Adoptive: methods
KW  - Immunotherapy, Adoptive: adverse effects
KW  - Graft vs Host Disease: etiology
KW  - Hematopoietic Stem Cell Transplantation: adverse effects
KW  - Hematopoietic Stem Cell Transplantation: methods
KW  - Male
KW  - Transplantation, Homologous
KW  - Female
KW  - Inflammation
KW  - Middle Aged
KW  - Cytokine Release Syndrome: etiology
KW  - Receptors, Chimeric Antigen: metabolism
KW  - Prospective Studies
KW  - Cytokine release syndrome (Other)
KW  - Graft versus host disease - GVHD (Other)
KW  - Immune related adverse event - irAE (Other)
KW  - Immunotherapy (Other)
KW  - Stem cell (Other)
KW  - LRG1 protein, human (NLM Chemicals)
KW  - Glycoproteins (NLM Chemicals)
KW  - LRG1 protein, mouse (NLM Chemicals)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40118496
DO  - DOI:10.1136/jitc-2024-009372
UR  - https://inrepo02.dkfz.de/record/300093
ER  -