Myosin specific TRM cells mediate increased severity of immune checkpoint inhibitor myocarditis

Abstract Immune checkpoint blockade has revolutionized the field of cancer immunotherapy; however, it has been also associated with immune-related adverse events (IRAE). Immune checkpoint inhibitor (ICI)-myocarditis occurs in approximately 1% of patients, however, it has a high fatality rate of up to 50%. To prevent life-threatening toxicities, it is imperative to understand what predisposes patients to ICI-myocarditis. We examined if previous cardiac injury increases an individual’s susceptibility to develop ICI-myocarditis. We demonstrated that ischemic injury substantially changes the phenotype of cardiac lymphocytes, causing them to upregulate the well-characterized tissue resident markers such as CD69 and CD103. We were excited to find that these cardiac tissue resident T (TRM) cells express prominent levels of the checkpoint molecule PD-1 and have high TCR specificity for cardiac myosin. TRM cells have been described in the literature to establish residency in non-lymphoid organs where they provide a rapid functional response more efficiently than circulating memory T cells. To investigate the role that cardiac TRM cells play in the occurrence of ICI-myocarditis, we developed a novel two-hit model. In this model cardiac injury is induced through ischemic injury (first hit), mice are allowed to recover before we begin the administration of immune checkpoint antibodies (second hit). Our data suggest that after the administration of PD-1 blocking antibodies, mice with myosin specific TRM cells are more susceptible to ICI-myocarditis. Further characterization of cardiac TRM cells could provide insight into why checkpoint mediated cardiac toxicities are particularly rapid and have high fatality rates.