Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Transcriptomics of Immune checkpoint inhibitor-associated myocarditis patients reveal inflammasome pathway activation
D. Finke1, M. Heckmann1, J. Salatzki1, L. Heinzerling2, B. Meder1, M. Völkers1, O. J. Müller3, N. Frey1, H. A. Katus1, F. Leuschner1, Z. Kaya1, L. H. Lehmann1
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Dermatologie, Erlangen; 3Klinik für Innere Medizin III, Schwerpunkt Kardiologie und Angiologie, Universitätsklinikum Schleswig-Holstein, Kiel;

The prognosis of many oncological diseases was dramatically improved by the use of immune checkpoint inhibitors (ICIs). Nevertheless, their broad utilization leads to an increase of immune related adverse events (irAEs). The ICI-associated myocarditis (ICIM) is a rare, but severe irAE. Diagnostic as well as therapeutic options of ICIM are limited. We aimed to characterize the transcriptional consequences of ICIM in patients’ biopsies in order to explore unique, ICIM-defining genes and pathways. 

We observed an heterogenous clinical presentation of patients with ICIM (n=19), including asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), reductions of the left ventricular ejection fraction or signs and symptoms of heart failure or acute coronary syndrome.

We compared transcriptional changes of ICIM (n=9) with samples from dilatative cardiomyopathy (DCM, n=11), virus-induced myocarditis (VIM, n=5) and with samples of patients receiving ICIs without confirmed evidence of myocarditis (n=4) in bulk-RNA-seq.

We found 3784 upregulated genes in ICIM (FDR<0.05) compared VIM or DCM. Within those genes, we identified an ICIM-defining gene pattern. Most upregulated genes included guanylate binding protein 5 and 6 (compared to VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)). Both are prominent members of the interferon-gamma (IFNg) pathway and crucial for the assembly  of the inflammasome. Histological assessments of ICIM-patients’ biopsies revealed an upregulation of GBP5 and GBP6 in cardiomyocytes.

Ongoing in-vitro and in-vivo models on the role of GBP5 in ICIM will help us to understand the cardiac inflammatory response in more detail. IFNg-dependent genes and the regulation of the inflammasome may be additional targets for a specific cardiac treatment of patients with ICIM. 


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