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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Veröffentlicht in:Cancers 2021-05, Vol.13 (10), p.2498
Hauptverfasser: Finke, Daniel, Heckmann, Markus B, Salatzki, Janek, Riffel, Johannes, Herpel, Esther, Heinzerling, Lucie M, Meder, Benjamin, Völkers, Mirko, Müller, Oliver J, Frey, Norbert, Katus, Hugo A, Leuschner, Florian, Kaya, Ziya, Lehmann, Lorenz H
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Sprache:eng
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Zusammenfassung: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 ( = 9) with samples from dilated cardiomyopathy (DCM, = 11), virus-induced myocarditis (VIM, = 5), and with samples of patients receiving ICIs without any evidence of myocarditis ( = 4). Patients with ICIM ( = 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13102498