Abstract 623 Guanylate binding protein 5 (GBP5) is a cardiomyocyte-expressed target of Immune Checkpoint Inhibitor-associated myocarditis

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Guanylate binding protein 5 (GBP5) is a cardiomyocyte-expressed target of Immune Checkpoint Inhibitor-associated myocarditis
V. Sanders¹, D. Finke¹, M. Heckmann¹, N. Frey¹, L. H. Lehmann¹
¹Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg;
Targeting immune checkpoints is a novel approach in cancer therapy. Nevertheless, the broad use of immune checkpoint inhibitors (ICIs) leads to an increase in immune related adverse events (irAEs). The ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate of up to 50%. Until now, the pathomechanism of ICIM is not well understood and the diagnostic and therapeutic strategies are limited. Via comparative transcriptomics of human myocardial biopsies of ICIM patients (n=9), we were able to identify an ICIM-specific gene pattern, including interferon gamma responsive genes, such as guanylate-binding protein 5 and 6 (GBP5/6). We aim to further characterize the underlying mechanism in ICIM by developing an in vitro model to gain further insight in the cardiomyocyte-specific ICIM-defining pathways. We co-cultured neonatal rat ventricular cardiomyocytes (NRVMs) with human peripheral blood mononuclear cells (hPBMCs; n=3) from healthy donors ± pre-incubation with the PD-1 inhibitor (PD1i) Pembrolizumab. We observed elevated troponins in the supernatant of samples that were co-cultured with PD1i+hPBMCs (PBMC+PD1i hs-cTnT: mean±SEM: 16921.25±2524.65 ng/l, hPBMC alone hs-cTnT: mean±SEM: 4609.50±188.13 ng/l, p=0.0286; Mann-Whitney-Test). This indicates a PDi-dependent cytotoxicity of hPBMCs on NRVMs. On a transcriptional level, we were able to confirm GBP5 to be regulated in cardiomyocytes (fc hPBMC+PD1i/hPBMC co-cultures = 2.12, p=0.0286, Mann-Whitney Test). Via RNA sequencing and bioinformatical analysis (human genome-mapping and rat-genome mapping) we characterized the gene-wide transcriptional changes in hPBMCs and NRMVs of our in vitro model and found potential novel targets including e.g. PDE9a (log2fc PMBC+PD1i/hPBMC: 1.52, FDR<0.05). By comparing the results with the biopsies of ICIM-patients, GBP5 stands out-as an important cardiomyocyte-specific target in ICIM. For further studies we currently combine GBP5 knockdown in vitro with in-vivo experiments in a new generated cardiomyocytes specific GBP5-knockout mouse. This will further reveal the role of GBP5 in ICIM.
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