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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Cancers - 13(2021), 10 vom: 20. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Finke, Daniel [VerfasserIn] |
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| Links: |
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| Themen: |
CD8 |
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| Anmerkungen: |
Date Revised 05.06.2021 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/cancers13102498 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM326139133 |
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| 100 | 1 | |a Finke, Daniel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation |
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| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a CTLA4 | |
| 650 | 4 | |a ICI-associated myocarditis | |
| 650 | 4 | |a ICIM | |
| 650 | 4 | |a PD1 | |
| 650 | 4 | |a PDL-1 | |
| 650 | 4 | |a comparative transcriptomics | |
| 650 | 4 | |a virus myocarditis | |
| 700 | 1 | |a Heckmann, Markus B |e verfasserin |4 aut | |
| 700 | 1 | |a Salatzki, Janek |e verfasserin |4 aut | |
| 700 | 1 | |a Riffel, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Herpel, Esther |e verfasserin |4 aut | |
| 700 | 1 | |a Heinzerling, Lucie M |e verfasserin |4 aut | |
| 700 | 1 | |a Meder, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Völkers, Mirko |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Oliver J |e verfasserin |4 aut | |
| 700 | 1 | |a Frey, Norbert |e verfasserin |4 aut | |
| 700 | 1 | |a Katus, Hugo A |e verfasserin |4 aut | |
| 700 | 1 | |a Leuschner, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Kaya, Ziya |e verfasserin |4 aut | |
| 700 | 1 | |a Lehmann, Lorenz H |e verfasserin |4 aut | |
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