The role of tumor expression of alpha-myosin in immune checkpoint inhibitor-associated myocarditis

Vanderbilt University, Nashville TN

Investigators

Abstract

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer therapy by unleashing the body's natural defenses to fight against tumors. However, this potent immunotherapeutic approach is not without its drawbacks, as it can trigger immune-related adverse events (irAEs), including potentially life- threatening myocarditis. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood, but recent evidence from our lab and others suggests a crucial link to α-myosin, a cardiac muscle protein that is abnormally expressed in some cancer cells. In this proposal, I seek to extensively investigate the role of tumor- expressed α-myosin in the development of ICI-MC. My proposal is based on the central hypothesis that tumor expression of α-myosin can activate T cells specific to this antigen, driving an autoimmune response that culminates in myocarditis. To test this hypothesis, I will conduct a series of experiments involving mouse models bearing tumors that do or do not have enforced expression of α-myosin. I will compare the rate and severity of ICI-MC in these mice to that in mice bearing tumors without α-myosin expression. To assess the potential of using tumor-expressed α-myosin as a biomarker to predict the development of ICI-MC, I will analyze RNA and protein expression levels of α-myosin in tumor tissues from patients who developed ICI-MC compared to those who did not. I will further elucidate the mechanism through which the immune system interacts with tumor cells through innovative in vitro and in vivo approaches. In vitro, I will perform co-culture assays to establish whether cancer cells expressing α-myosin can effectively present this antigen and activate T cells. To validate the T cell activating capacity of α-myosin-expressing tumors in vivo, I will infuse fluorescently labeled T cells expressing T cell receptors specific for α-myosin into mice bearing tumors expressing this antigen, and track clonal expansion across tissue sites (heart, tumor, peripheral blood, lymph nodes). My approach is innovative in that it will be the first study to focus on features of tumor biology, such as expression of α-myosin, that are associated with an increased risk of ICI-MC. The potential impact of this research is significant. In completing this proposal, I will deliver urgently needed insights into the pathophysiology of ICI-MC, with the potential to unveil new approaches for screening and prevention of the disease. If a definitive association between tumor expression of α-myosin and the development of ICI-MC can be made, this could serve as a much-needed biomarker to identify patients at risk of developing this severe irAE. It would also provide a foundation for the development of new strategies to prevent irAEs in patients undergoing ICI therapy. This research could contribute to a broader understanding of the immune response to cancer therapy, ultimately enhancing the efficacy and safety of ICIs for a wide variety of cancer patients. Furthermore, the completion of this project will facilitate the development of my technical, critical thinking, and communication skills that will be crucial to my success as an independent physician-scientist.