Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Ian Pizzo, Benedicte Charmeteau-De Muylder, Alban Redheuil, Florence Tubach, Jacques Cadranel, Audrey Milon, Stéphane Ederhy, Thomas Similowski, Douglas B Johnson, Rémi Cheynier, Toniemarie Catalan, Olivier Benveniste, Salim S Hayek, Yves Allenbach, Michelle Rosenzwajg, Charles Dolladille, Joe-Elie Salem, Lorenz H Lehmann, Baptiste Abbar, Samia Boussouar, Marie Bretagne, John R Power, Javid J Moslehi, Paul Gougis, Damien Amelin, Agnès Dechartres, Charlotte Fenioux, Pierre-Yves Courand, Jennifer Cautela, Joachim Alexandre, Adrien Procureur, Antoine Rozes, Sarah Leonard-Louis, Juan Qin

Journal: Nature medicine 2023;29(12):3100-3110

PMID: 37884625

Full Text on Nature Publishing Group View on PubMed

Abstract

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Address: Sorbonne Université, INSERM, CIC-1901 Paris-Est, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.; Hôpitaux de Paris, Henri Mondor Hospital, Department of Oncology, Créteil, France.; Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Oncology, Paris, France.; Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Radiology, Paris, France.; Department of Medecine, University of California, San Diego, San Diego, CA, USA.; Department of Medecine, University of California, San Francisco, San Francisco, CA, USA.; Sorbonne Université, INSERM, Association Institut de Myologie, Center of Research in Myology, UMRS 974, Paris, France.; Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Département de Santé Publique, Centre de Pharmacoépidémiologie (Cephepi), Unité de Recherche Clinique PSL-CFX, CIC-1901, AP-HP, Hôpital Pitié Salpêtrière, Paris, France.; Department of Cardiology, University Hospital Heidelberg; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Fédération de Cardiologie, IMMUCARE, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon; Université de Lyon, CREATIS UMR INSERM U1044, INSA, Lyon, France.; Aix-Marseille University, University Mediterranean Center of Cardio-Oncology, Unit of Heart Failure and Valvular Heart Diseases, Center for Cardiovascular and Nutrition Research, INSERM 1263, INRAE 1260, Nord Hospital, Assistance Publique-Hôpitaux de Marseille, Paris, France.; CHU de Caen Normandie, Department of Pharmacology, Pharmacoepidemiology Unit; Normandie Université, UNICAEN, INSERM U1086 ANTICIPE Centre François Baclesse, Caen, France.; Hôpitaux de Paris, Pitié Salpêtrière Hospital, Laboratoire de Neuropathologie, Paris, France.; Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France.; Hôpitaux de Paris, Tenon Hospital, Department of Pulmonology and Thoracic Oncology and GRC Theranoscan Sorbonne University, Paris, France.; Hôpitaux de Paris, Tenon Hospital, Department of Radiology, Paris, France.; Hôpitaux de Paris, Saint-Antoine Hospital, Department of Cardiology, Paris, France.; Sorbonne Université, INSERM, UMRS 1158 Neurophysiologie respiratoire expérimentale et clinique'; Assistance Publique -Hôpitaux de Paris, Pitié-Salpêtrière Hospital, 'Département R3S', Paris, France.; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.; Department of Internal Medicine, Sorbonne University, AP-HP, INSERM UMRS 974, Pitié-Salpêtrière Hospital, Paris, France.; Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Immunology, Paris, France.; Sorbonne Université, INSERM, CIC-1901 Paris-Est, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France. [email protected].; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].

DOI: 10.1038/s41591-023-02591-2

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MeSH Terms: Humans, Immune Checkpoint Inhibitors, Myocarditis, Antineoplastic Agents, Immunological, Myotoxicity, Myositis, Neoplasms