SEP 01, 2020 8:00 AM PDT

Single-cell analyses of checkpoint-inhibition-induced myocarditis: implications into mechanisms of severe immune-related adverse events

Speaker
  • Pharm.D., Ph.D. Associate Professor, Departments of Medicine and Pathology, Microbiology and Immunology Vanderbilt University Medical Center
    Biography
      Dr. Balko received his Pharm.D. from the State University of New York College at Buffalo, and his Ph.D. from the University of Kentucky, studying Cancer Pharmacogenomics. He is currently Associate Professor, Departments of Medicine and Pathology, Microbiology and Immunology at Vanderbilt University Medical Center. His translational cancer research is focused on molecular therapeutics, onco-immunology & bioinformatics. His laboratory is focused on improving treatment outcomes in breast cancer (particularly triple-negative breast cancer) and other solid tumors through translational approaches. To accomplish this, they integrate data from genomic and molecular profiling studies with molecular biology and signal transduction methodologies to identify altered pathways in cancer, the functional consequences of these alterations, and ways to directly target them in patients to improve clinical outcomes and survival.

    Abstract
    DATE:  September 1, 2020
    TIME:   8:00am PT, 11:00am ET
     
    Nearly half of all cancer patients are eligible to receive treatment with immune checkpoint inhibitors (ICI). Thus, preventing, identifying and treating immune-related adverse events (irAEs) are urgent challenges. Myocarditis is an uncommon irAE, affecting <1% of ICI-treated patients, but has a mortality rate of nearly 50%. To study the mechanisms of ICI-myocarditis, we used a mouse model in which a combination of checkpoint gene KO causes premature death due to myocarditis. By flow cytometry, the myocardial immune infiltrate was primarily composed of CD8+ T cells and CD68+ macrophages, akin to subjects with ICI-associated myocarditis, and anti-CD8 depleting antibodies rescued survival. Single-cell RNA-seq of heart tissue identified highly activated, clonal CD8+ T cells. TCR sequencing also demonstrated highly clonal, but private, TCRs in affected mice. Computational analysis revealed high structural similarity in these TCRs, suggestive of similar antigen binding. TCR sequencing of two subjects who died with ICI-myocarditis also showed high clonality in the heart. Antigen discovery efforts are underway to yield new insights into the pathophysiology of this irAE. For Research Use Only. Not for use in diagnostic procedures.
     
    Learning Objectives:
    • Immune-related adverse events and myocarditis (case series)
    • Describe murine models that replicate human checkpoint inhibitor-associated myocarditis
    • Describe implementation of single-cell technologies and flow cytometry to evaluate the inflammatory microenvironment in the murine model
     
     
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