| アブストラクト | BACKGROUND: Myocarditis is a severe complication of immune checkpoint inhibitors (ICIs). The major risk factor for ICI myocarditis is the use of combination ICI treatment, especially when relatlimab, a novel anti-LAG-3 (lymphocyte-activation gene 3) antibody, is combined with anti-PD-1 (programmed cell death protein 1) therapy. Although pathogenic T cells are necessary for ICI myocarditis, the specific signaling and T-cell populations that drive cardiac infiltration have not been fully elucidated, especially in setting of anti-LAG-3/PD-1 treatment. METHODS: We used VigiBase, an international pharmacovigilance database, to assess the risk of myocarditis with anti-LAG-3 compared with other ICI treatment regimens. We identified a mouse model of LAG-3/PD-1-associated ICI myocarditis through genetic deletion of immune checkpoints LAG-3 and PD-1 (Lag3(-/-), Pdcd1(-/-) mice) and performed rigorous cardiac phenotyping using histology, flow cytometry, electrocardiography, single-cell RNA sequencing, and antibody-induced cellular depletion. RESULTS: We found an increased risk of myocarditis with anti-LAG-3 combination treatment clinically, confirming early clinical trial data. Lag3(-/-), Pdcd1(-/-) mice were found to develop severe cardiac inflammation by histology with increased cardiac macrophages and clonal T cells, which was associated with the development of spontaneous arrhythmias leading to premature death by 6 to 8 weeks. We identified CXCR6 (C-X-C motif chemokine receptor 6) as a key marker of activated cardiac T cells in this model, along with analogous signals in other preclinical models and patient data. CXCR6 marked a heterogenous group of cardiac T cells, including distinct clusters of Gzmk, Gzmb, Cd4, and actively dividing T cells. CXCL16 (C-X-C motif chemokine ligand 16), the sole known ligand for CXCR6, was similarly upregulated in the cardiac macrophage population. Treatment with anti-CXCR6 antibody prevented premature lethality, attenuated arrhythmias, and reduced the histological severity of myocarditis, demonstrating that CXCR6(+) T cells are necessary for disease pathogenesis. CONCLUSIONS: Our findings suggest that ICI myocarditis is driven by an expansion of CXCR6(+) T cells and identifies CXCR6 as a putative therapeutic target for this highly morbid condition. |
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| ジャーナル名 | Circulation |
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| Pubmed追加日 | 2026/1/7 |
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| 投稿者 | Munir, Amir Z; Gutierrez, Alan; Krawiec, Cade J; Manandhar, Priyanka; Shyani, Anya C; Ma, Pan; Gougis, Paul; Baylis, Richard A; Hou, Lifei; Remold-O'Donnell, Eileen; Balko, Justin M; Salem, Joe-Elie; Lavine, Kory J; Lichtman, Andrew H; Qin, Juan; Moslehi, Javid J |
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| 組織名 | Section of Cardio-Oncology & Immunology, Cardiovascular Research Institute,;School of Medicine, University of California San Francisco (A.Z.M., A.G., C.J.K.,;P. Manandhar, A.C.S., R.A.B., J.Q., J.J.M.).;Cardiovascular Division, Department of Medicine, Washington University School of;Medicine, St Louis, MO (P. Ma, K.J.L.).;Department of Medical Oncology, AP-HP, Institut Universitaire de Cancerologie,;INSERM U1136, CLIP2 Galilee (P.G.), Pitie-Salpetriere University Hospital,;Sorbonne Universite, France.;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's;Hospital, MA (L.H.).;Department of Anaesthesia (L.H.), Harvard Medical School, Boston, MA.;Edelweiss Immune Inc, Cambridge, MA (E.R.-O.).;Department of Medicine, Department of Pathology, Microbiology and Immunology,;Vanderbilt University Medical Center, Nashville, TN (J.M.B.).;Clinical Investigation Center Paris-Est, CIC-1901/INSERM, Department of;Pharmacology (J.-E.S.), Pitie-Salpetriere University Hospital, Sorbonne;Universite, France.;Department of Pathology, Brigham and Women's Hospital (A.H.L.), Harvard Medical;School, Boston, MA. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/41498147/ |
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