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.
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Data availability
VigiBase is publicly accessible at https://www.vigiaccess.org/. Access to the ICI myocarditis international REDCap (hosted by Vanderbilt University Medical Center) is possible for contributors after regularization of ethical and contractual considerations among institutions. Clinical datasets used for the biological and radiological sub-studies would be made available upon reasonable request and in compliance with the European General Data Protection Regulation to the corresponding author within 1 month.
Change history
03 January 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41591-023-02771-0
27 November 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41591-023-02690-0
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Acknowledgements
The University of Michigan ICI Biobank was made possible by generous philanthropic support from Mr. John Janitz.
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Conception (J.E.S.); Data collection (all); Analysis (C.F., P.G., S.B., B.A., C.D., J.E.S and F.T.); Writing of the first draft (J.E.S.); Editing (all); Funding (J.E.S. and S.S.H.).
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None directly related to this work. However, B. Abbar has received consultant or advisory role fees or meeting invitations from Novartis, Astellas, Sanofi, AstraZeneca, Janssen, Merck Sharp & Dohme, Pfizer, IPSEN Pharma and Takeda. J. J. Moslehi is supported by National Institutes of Health grants R01HL141466, R01HL155990, R01HL156021 and R01HL160688 and has served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Takeda, AstraZeneca, Myovant, Kiniksa Pharmaceuticals, BeiGene and Cytokinetics. L.H.L. has served on advisory boards for Daiichi Sankyio, Senaca, AstraZeneca and Servier; has served as an external expert for AstraZeneca; has received speakers’ honoraria from Novartis and Merck Sharp & Dohme; and is receiving grants from the German Center for Cardiovascular Research (DZHK) and the German Research Foundation (DFG) (LE3570/2-1 and 3570/3-1) and grant 01KC2006B from the Federal Ministry for Education and Research (BMBF). J. Cautela has received consultant or advisory role fees or meeting invitations from Novartis, Sanofi, AstraZeneca, Janssen, Merck Sharp & Dohme and Pfizer. F. Tubach is head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique Hôpitaux de Paris and of the Clinical Research Unit of Pitié-Salpêtrière Hospital; both of these institutions have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies that have contributed variously to small parts of the salaries of its employees. F. Tubach is not employed by these institutions and did not receive any personal remuneration from these companies. J. Cadranel has served on advisory boards or as a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Takeda, Pfizer and Sanofi and has received research funding from AbbVie, Pfizer and Sanofi. D. Johnson has served on advisory boards or as a consultant for Bristol-Myers Squibb, Catalyst Biopharma, Iovance, Janssen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax and Teiko; has received research funding from Bristol-Myers Squibb and Incyte; and has patents pending for the use of MHC-II as a biomarker for ICI response and for abatacept as treatment for immune-related adverse events. T. Similowski reports personal fees for consulting and teaching activities from AstraZeneca France, Chiesi France, KPL Consulting, Lungpacer, OSO-AI, TEVA France and Vitalaire. He is a stock shareholder of startups Hephaï and Austral Dx. J.-E. Salem has participated on advisory boards and been a consultant for or received grants from Bristol-Myers Squibb, Novartis, AstraZeneca, CRC Oncology, EISAI and BeiGene. S.S.H. is supported by National Heart, Lung, and Blood Institute R01HL153384 and National Institute of Diabetes and Digestive and Kidney Diseases R01-DK128012. Y.A. was supported by the ARC Foundation. Other authors have nothing to disclose.
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Ten Supplementary Data Files and an appendix with all contributors/institutions of the international ICI myocarditis registry
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Fenioux, C., Abbar, B., Boussouar, S. et al. Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis. Nat Med 29, 3100–3110 (2023). https://doi.org/10.1038/s41591-023-02591-2
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DOI: https://doi.org/10.1038/s41591-023-02591-2
