Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis

IF 58.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Nature Medicine Pub Date : 2023-10-26 DOI:10.1038/s41591-023-02591-2
Charlotte Fenioux, Baptiste Abbar, Samia Boussouar, Marie Bretagne, John R. Power, Javid J. Moslehi, Paul Gougis, Damien Amelin, Agnès Dechartres, Lorenz H. Lehmann, Pierre-Yves Courand, Jennifer Cautela, Joachim Alexandre, Adrien Procureur, Antoine Rozes, Sarah Leonard-Louis, Juan Qin, International ICI-Myocarditis Registry, Rémi Cheynier, Benedicte Charmeteau-De Muylder, Alban Redheuil, Florence Tubach, Jacques Cadranel, Audrey Milon, Stéphane Ederhy, Thomas Similowski, Douglas B. Johnson, Ian Pizzo, Toniemarie Catalan, Olivier Benveniste, Salim S. Hayek, Yves Allenbach, Michelle Rosenzwajg, Charles Dolladille, Joe-Elie Salem
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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. Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.

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胸腺改变与免疫检查点抑制剂心肌炎易感性。
免疫检查点抑制剂(ICI)已经改变了肿瘤学的治疗格局。然而,ICI可以诱导罕见的危及生命的自身免疫性T细胞介导的肌毒性,包括心肌炎和肌炎。胸腺在T细胞成熟过程中起着至关重要的作用。在这里,我们证明胸腺改变与ICI肌肉毒性的发生率和严重程度增加有关。首先,使用国际药物警戒数据库VigiBase、巴黎索邦大学辅助公共图书馆数据仓库(法国巴黎)和临床试验的荟萃分析,我们发现ICI治疗胸腺上皮肿瘤(TET,尤其是胸腺瘤)比其他ICI治疗的癌症更常与ICI肌肉毒性相关。其次,在国际ICI心肌炎登记中,我们确定,与其他癌症相比,TET患者(包括TET活动史或既往史)在ICI开始后心肌炎发生得更早,并且在危及生命的心律失常和并发肌炎方面更为严重,导致呼吸肌衰竭和死亡。最后,我们发现抗乙酰胆碱受体抗体(胸腺相关自身免疫的生物学指标)在ICI心肌炎患者中比在ICI治疗的对照患者中更普遍。总之,我们的研究结果强调,胸腺改变与ICI肌肉毒性的发生率和严重程度有关。评估胸腺的临床放射生物学检查可能有助于预测ICI的肌肉毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nature Medicine
Nature Medicine 医学-生化与分子生物学
CiteScore
100.90
自引率
0.70%
发文量
525
审稿时长
1 months
期刊介绍: Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.
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