Abstract P2174: Transcriptomic Profiling Of Immune Checkpoint Inhibitor Myocarditis Reveals Novel Therapeutic Targets

Abstract

Introduction: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of advanced cancers. However, the increased use of ICI has also resulted in a higher incidence of ICI-related cardiovascular side effects, including myocarditis, which has a high mortality rate of nearly 50%. Understanding the mechanisms underlying ICI-related cardiotoxicity is essential for identifying new therapeutic targets and improving patient survival. Hypothesis: We hypothesized that ICI-myocarditis has a unique transcriptomic profile that could be used to identify new drug targets. Methods: To test our hypothesis, we isolated RNA from our ICI-myocarditis mouse hearts and performed RNA-seq using the Illumina NovaSeq 6000. We also reanalyzed a human IC-myocarditis dataset downloaded from the Gene Expression Omnibus database. Results: Our results demonstrated that in both our animal models and patients, the upregulated pathways in ICI myocarditis heart tissues were enriched for regulation of T cell activation, leukocyte adhesion, and multiple cytokine signaling pathways. Conversely, downregulated pathways included those involved in cellular respiration, oxidative phosphorylation, and cardiac conduction. The most significantly upregulated genes were involved in innate and adaptive immune responses, including the CD8-dependent gene program and response to interferon-gamma of macrophages. By querying the Drug Gene Interaction Database, we identified several novel biologically plausible therapeutic targets. Correspondingly, a number of FDA-approved drugs were revealed, including monoclonal or chimeric antibodies such as Tocilizumab and Alemtuzumab, recombinant proteins like Abatacept and Anakinra, as well as small molecules such as Ruxolitinib and Imiquimod. Conclusions: Our study is the first to use the entire transcriptomic profile of ICI myocarditis in both preclinical models and patients for drug discovery. Our results demonstrate that ICI myocarditis has a distinct gene expression profile compared to healthy and other cardiac diseases. By querying a drug-gene interaction database, we identified several novel drug targets and possible treatments for ICI-related cardiotoxicity.