Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy
Background 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 pr...
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BMJ Publishing Group
2025-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/3/e009372.full |
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| author | John Greenwood Petra Knaus Stephen Moss Olaf Penack Lars Bullinger Sarah Mertlitz Katarina Riesner Martina Kalupa Nora Uhlig Steffen Cordes Lydia Verlaat Mina Jamali Ningyu Li Hadeer Mohamed Elsayed Rasheed Mohamed Jerome Jatzlau Pedro Vallecillo-Garcia |
| author_facet | John Greenwood Petra Knaus Stephen Moss Olaf Penack Lars Bullinger Sarah Mertlitz Katarina Riesner Martina Kalupa Nora Uhlig Steffen Cordes Lydia Verlaat Mina Jamali Ningyu Li Hadeer Mohamed Elsayed Rasheed Mohamed Jerome Jatzlau Pedro Vallecillo-Garcia |
| author_sort | John Greenwood |
| collection | DOAJ |
| description | Background 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.Methods We investigated LRG1 in preclinical models and in patient samples.Results 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.Conclusions 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. |
| format | Article |
| id | doaj-art-b3c5029fac094daa973de889d7e3a805 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b3c5029fac094daa973de889d7e3a8052025-08-20T02:42:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-03-0113310.1136/jitc-2024-009372Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapyJohn Greenwood0Petra Knaus1Stephen Moss2Olaf Penack3Lars Bullinger4Sarah Mertlitz5Katarina Riesner6Martina Kalupa7Nora Uhlig8Steffen Cordes9Lydia Verlaat10Mina Jamali11Ningyu Li12Hadeer Mohamed Elsayed Rasheed Mohamed13Jerome Jatzlau14Pedro Vallecillo-Garcia15Institute of Ophthalmology, University College London, London, UKInstitute of Chemistry and Biochemistry, Freie Universitaet Berlin, Berlin, GermanyInstitute of Ophthalmology, University College London, London, UKDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyGerman Cancer Consortium (Deutsches Konsortium Für Translationale Krebsforschung, DKTK), Partner Site, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyBerlin Center for Translational Vascular Biomedicine, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyBerlin Center for Translational Vascular Biomedicine, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyInstitute of Chemistry and Biochemistry, Freie Universitaet Berlin, Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyBackground 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.Methods We investigated LRG1 in preclinical models and in patient samples.Results 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.Conclusions 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.https://jitc.bmj.com/content/13/3/e009372.full |
| spellingShingle | John Greenwood Petra Knaus Stephen Moss Olaf Penack Lars Bullinger Sarah Mertlitz Katarina Riesner Martina Kalupa Nora Uhlig Steffen Cordes Lydia Verlaat Mina Jamali Ningyu Li Hadeer Mohamed Elsayed Rasheed Mohamed Jerome Jatzlau Pedro Vallecillo-Garcia Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy Journal for ImmunoTherapy of Cancer |
| title | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy |
| title_full | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy |
| title_fullStr | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy |
| title_full_unstemmed | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy |
| title_short | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy |
| title_sort | leucine rich α 2 glycoprotein 1 lrg1 during inflammatory complications after allogeneic stem cell transplantation and car t cell therapy |
| url | https://jitc.bmj.com/content/13/3/e009372.full |
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