Cytotoxic T cells specific for alpha-myosin drive immunotherapy related myocarditis

Abstract

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to immune checkpoint inhibitor (ICI) utility in anti-cancer therapy1. The pathogenesis of ICI-myocarditis is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathologic features of ICI-myocarditis, including myocardial T cell infiltration2. Single cell RNA/T cell receptor (TCR) sequencing on the cardiac immune infiltrate of Pdcd1-/-Ctla4+/- mice identified activated, clonal CD8+ T cells as the dominant cell population. Treatment with anti-CD8, but not anti-CD4, depleting antibodies rescued survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients which required CD8+ T cells. Alpha-myosin, a cardiac specific protein absent from the thymus3,4, was identified as the cognate antigen source for three MHC-I restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from two patients with ICI-myocarditis were expanded by alpha-myosin peptides, and these alpha-myosin expanded T cells shared TCR clonotypes with diseased heart and skeletal muscles, indicating that alpha-myosin may be a clinically important autoantigen in ICI-myocarditis. These studies underscore the critical role for cytotoxic CD8+ T cells, are the first to identify a candidate autoantigen in ICI-myocarditis and yield new insights into ICI toxicity pathogenesis.

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

“…Recently, a preprint article highlights the importance of CD8 + T cells in a genetic murine model (Pdcd1−/−Ctla4+/−) that recapitulates clinicopathologic characteristics of ICI-myocarditis. They identified the alpha-myosin as a cardiac-specific antigen; peptides from this protein induce the expansion of peripheral blood T cells from two patients with ICI-myocarditis indicating its clinical importance ( Balko et al, 2022 ).…”

The role of immune checkpoints in cardiovascular disease

“…Another candidate for autoimmunity is alpha-myosin, a cardiac specific protein. A study in preprint on the pathogenesis of ICI-mediated myocarditis found that highly clonal TCRs from three independent murine cardiac TCR repertoires were able to recognize alpha-myosin epitopes ( Balko et al, 2022 ). Concordantly, alpha-myosin expanded T cells from the peripheral blood of two ICI-mediated myocarditis patients shared TCR clonotypes with diseased heart muscle, suggesting alpha-myosin to potentially be a clinically important autoantigen in ICI-mediated myocarditis.…”

An Immune Checkpoint Inhibitor Heart: How CD45RA + Effector Memory CD8 + T Cells (Temra) Are Implicated in Immune Checkpoint Inhibitor Myocarditis

“…Alpha myosin (MYH6, also known as MYHCA) was recently shown to be of relevance for patients with ICI myocarditis. 5 This may pave the way to more refined, antigen-specific T-cell solutions, such as engineered myosin-specific immunosuppressive chimeric antigen receptor-regulatory T cells, which could protect the heart while enabling other T cells to attack the tumor.…”

“…Supporting this, mouse model work has demonstrated that the disease is dependent on the presence of CD8 + T cells. 4,5 In addition, the expression of PD-L1 on myocardial tissue 1,4,6 suggests that the PD-1/PDL-1 axis may have a tolerance-promoting role in the heart, disrupted by ICI. Last, the finding of PD-1 expression on a cardiac cell subset likely to include peripheral regulatory T cells 3 may also provide an additional means through which anti–PD-1 could break immune tolerance in the heart.…”