{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T09:37:53Z","timestamp":1792575473164,"version":"4.5.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,3,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>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\u2013LAG-3 (lymphocyte-activation gene 3) antibody, is combined with anti\u2013PD-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\u2013LAG-3\/PD-1 treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We used VigiBase, an international pharmacovigilance database, to assess the risk of myocarditis with anti\u2013LAG-3 compared with other ICI treatment regimens. We identified a mouse model of LAG-3\/PD-1\u2013associated ICI myocarditis through genetic deletion of immune checkpoints LAG-3 and PD-1 (\n                      <jats:italic toggle=\"yes\">Lag3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">-\/<\/jats:italic>\n                        -\n                      <\/jats:sup>\n                      ,\n                      <jats:italic toggle=\"yes\">Pdcd1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">-\/<\/jats:italic>\n                        -\n                      <\/jats:sup>\n                      mice) and performed rigorous cardiac phenotyping using histology, flow cytometry, electrocardiography, single-cell RNA sequencing, and antibody-induced cellular depletion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We found an increased risk of myocarditis with anti\u2013LAG-3 combination treatment clinically, confirming early clinical trial data.\n                      <jats:italic toggle=\"yes\">Lag3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">-\/<\/jats:italic>\n                        -\n                      <\/jats:sup>\n                      ,\n                      <jats:italic toggle=\"yes\">Pdcd1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">-\/<\/jats:italic>\n                        -\n                      <\/jats:sup>\n                      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\n                      <jats:italic toggle=\"yes\">Gzmk<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Gzmb<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Cd4<\/jats:italic>\n                      , 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\n                      <jats:sup>+<\/jats:sup>\n                      T cells are necessary for disease pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that ICI myocarditis is driven by an expansion of CXCR6\n                      <jats:sup>+<\/jats:sup>\n                      T cells and identifies CXCR6 as a putative therapeutic target for this highly morbid condition.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.076976","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T10:00:15Z","timestamp":1767780015000},"page":"754-768","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["CXCR6\n                    <sup>+<\/sup>\n                    T Cells Drive Immune Checkpoint Inhibitor Myocarditis"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3512-5851","authenticated-orcid":true,"given":"Amir Z.","family":"Munir","sequence":"first","affiliation":[{"name":"Section of Cardio-Oncology &amp; 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9129-243X","authenticated-orcid":true,"given":"Alan","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Section of Cardio-Oncology &amp; 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5127-6938","authenticated-orcid":true,"given":"Cade J.","family":"Krawiec","sequence":"additional","affiliation":[{"name":"Section of Cardio-Oncology &amp; 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2868-5286","authenticated-orcid":true,"given":"Priyanka","family":"Manandhar","sequence":"additional","affiliation":[{"name":"Section of Cardio-Oncology &amp; 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya C.","family":"Shyani","sequence":"additional","affiliation":[{"name":"Section of Cardio-Oncology &amp; 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-849X","authenticated-orcid":true,"given":"Pan","family":"Ma","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO (P. Ma, K.J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3064-7043","authenticated-orcid":true,"given":"Paul","family":"Gougis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Assistance Publique \u2013 H\u00f4pitaux de Paris, Institut Universitaire de Canc\u00e9rologie, INSERM U1136, CLIP2 Galil\u00e9e (P.G.)"},{"name":"Piti\u00e9-Salp\u00eatri\u00e8re University Hospital, Sorbonne Universit\u00e9, France (P.G., J.-E.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-7920","authenticated-orcid":true,"given":"Richard A.","family":"Baylis","sequence":"additional","affiliation":[{"name":"Section of Cardio-Oncology &amp; 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8975-7795","authenticated-orcid":true,"given":"Lifei","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children\u2019s Hospital, MA (L.H.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen","family":"Remold-O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Edelweiss Immune Inc, Cambridge, MA (E.R.-O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-5974","authenticated-orcid":true,"given":"Justin M.","family":"Balko","sequence":"additional","affiliation":[{"name":"Department of Medicine, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN (J.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0331-3307","authenticated-orcid":true,"given":"Joe-Elie","family":"Salem","sequence":"additional","affiliation":[{"name":"Clinical Investigation Center Paris-Est, CIC-1901\/INSERM, Department of Pharmacology (J.-E.S.)"},{"name":"Piti\u00e9-Salp\u00eatri\u00e8re University Hospital, Sorbonne Universit\u00e9, France (P.G., J.-E.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1948-9945","authenticated-orcid":true,"given":"Kory J.","family":"Lavine","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO (P. 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