Abstract 15833: Immune Checkpoint Inhibitor Myocarditis Subtypes are Determined by a Cd8-dependent Transcriptional Program

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing clinical use leads to higher rates of adverse immune related events (irAEs). One of those irAEs is the ICI-induced myocarditis (ICIM) - a rare phenomenon with an estimated mortality rate of up to 50%. We aimed to characterize the molecular changes of ICIM which are not yet understood completely. Methods: 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 dilatative cardiomyopathy (DCM, n=11) and virus-induced myocarditis (VIM, n=5). Results: Clinical analysis of 19 patients with ICIM showed an inconsistent presentation, e.g. an elevation of cardiac biomarkers (hsTnT, NT-proBNP, CK), a drop in leftventricular ejection fraction or late gadolinium enhancement in cMRI. We found 3784 (FDR <0.05) upregulated genes in ICIM. Among the genes that were related to antigen presentation and processing, we mainly found an upregulation of CD8. CD8-dependent clustering of ICI-patients, on the other hand, was associated with a number of immune cell-specific genes (compared to VIM: CXCL11 (log2 fc 3.24), CXCL9 (log2 fc 4.37), GBP6 (log2 fc 5.37), GBP5 (log2 fc 3.21). Analysis of high- and low-expressing CD8 positive biopsies identified two expression patterns, suggesting different pathological mechanisms for ICIM. Conclusion: Taken together, we were able to identify CD8 and CD8-associated genes as specifically regulated transcripts in ICIM. Moreover, based on the variable clinical phenotype, we propose that analysis of CD8 and CD8-dependent genes will be important to identify ICIM patients and to potentially sub-differentiate different phenotypes.