Though immunotherapy has been extending the lives of many patients with cancer, for a small number it has had an alarming but unexplained side effect: myocarditis. To investigate its pathogenesis, a research team led by Harvard Medical School analyzed immune responses in heart, blood, and tumor tissues from 28 patients who developed myocarditis on immune checkpoint inhibitor (ICI) treatment and 41 ICI-treated controls. The researchers used single-cell RNA sequencing, T-cell receptor (TCR) sequencing, microscopy, and proteomics to investigate the molecular pathways of ICI-related heart inflammation.
In the study, published in Nature, the researchers described increased cytotoxic T-cell presence alongside inflammatory dendritic cells and fibroblasts in patients with myocarditis-affected heart tissue. Meanwhile, blood analysis revealed lower plasmacytoid dendritic cell and B-cell levels in myocarditis patients.
T-cell receptors abundant in the affected heart tissue were distinct from those seen in tumors, contrary to previous research that suggested that the immune responses in a patient’s heart and tumor were the same. The team also found that the T-cell receptors did not recognize the α-myosin protein – responsible for heart-muscle contraction – which was previously reported to be a pivotal antigen driving checkpoint myocarditis. More work is needed to identify the particular antigens at play in the heart and the tumor.
The study's co-first author, Steven Blum, commented, “Because the responses in the tumor and the heart are different, it makes us hopeful that we can someday disentangle the two and treat them separately.” If so, potentially life-saving immunotherapy could continue whilst targeted treatments could be used to address myocarditis.
The research also highlights potential biomarkers of ICI-related myocarditis, such as specific TCR clones in circulating T-cells associated with fatal cases, which could aid in the future development of a blood-based test to help identify patients at higher risk.
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