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Comparative transcriptomics of immune checkpoint inhibitor myocarditis identifies guanylate binding protein 5 and 6 dysregulation

Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcript...

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Main Authors: Finke, Daniel (Author) , Heckmann, Markus B. (Author) , Salatzki, Janek (Author) , Riffel, Johannes (Author) , Herpel, Esther (Author) , Heinzerling, Lucie M. (Author) , Meder, Benjamin (Author) , Völkers, Mirko (Author) , Müller, Oliver J. (Author) , Frey, Norbert (Author) , Katus, Hugo (Author) , Leuschner, Florian (Author) , Kaya, Ziya (Author) , Lehmann, Lorenz (Author)
Format: Article (Journal)
Language:English
Published: 20 May 2021
In: Cancers
Year: 2021, Volume: 13, Issue: 10, Pages: 1-15
ISSN:2072-6694
DOI:10.3390/cancers13102498
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers13102498
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6694/13/10/2498
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Author Notes:Daniel Finke, Markus B. Heckmann, Janek Salatzki, Johannes Riffel, Esther Herpel, Lucie M. Heinzerling, Benjamin Meder, Mirko Völkers, Oliver J. Müller, Norbert Frey, Hugo A. Katus, Florian Leuschner, Ziya Kaya and Lorenz H. Lehmann

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520 |a Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway ‘response to interferon-gamma’, we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM. 
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