Background Myocarditis from immune checkpoint inhibition (ICI) has been reported in 0.04–1.14% of patients on ICI, with mortality up to 50%.1 Murine models reveal cardiac-myosin-specific T cells contribute to ICI-myocarditis; genetic/phenotypic differences may predispose to their activity.2 We present the Montreal Immune-Related Adverse Events (MIRAE) ICI-myocarditis project, conducted by an interdisciplinary team of physicians and scientists to understand molecular drivers of ICI-myocarditis.
Methods This case-control study comprises three groups of patients treated with ICI: 1) ICI-myocarditis; 2) non-ICI troponemia (elevated troponins from non-immune etiology); and 3) controls matched by tumour type, with no IRAEs nor troponemia. We analyzed blood samples from prior to ICI, at time of troponemia, or at 3–6 months after ICI initiation if no troponemia. We developed a multi-omics pipeline to understand mechanisms of ICI-myocarditis (figure 1), with immune cell subpopulation profiling of peripheral blood mononuclear cells (PBMCs) using single cell RNA and T/B cell receptor sequencing. This is validated with genomic DNA methylation, cytokine analyses, and PhenoCycler spatial single-cell imaging proteomics to localize cellular sources of upregulated cytokines and to visualize cell-cell interactions underpinning cardiac pathology.
Results Of 473 patients treated with ICI in the MIRAE biobank, 3.59% had ICI-myocarditis. Of these, 19 had stored samples and were included in this study (see table 1 for baseline characteristics). 5 patients (26%) developed arrhythmias. 10 (53%) had concurrent IRAE. 1 (5%) died from concurrent IRAE. There were no deaths from myocarditis. Elevations of blood neutrophil-to-lymphocyte ratio, alanine transaminase, and aspartate aminotransferase were associated with ICI-myocarditis, compared to non-myocarditis patients at 3–6 months on ICI (figure 2). Plasma cytokine profiling of 13 ICI-myocarditis cases and matching controls demonstrated no significant differences in baseline cytokines prior to ICI. Significant elevations of chemokine IP10 and anti-inflammatory cytokine IL10 were detected at time of myocarditis, implicating various immune cells, including T lymphocytes and monocytes (figure 3). Immune cell subpopulation profiling of PBMCs is ongoing (figure 4). Spatial profiling of the first ICI-myocarditis biopsy demonstrated T cell and macrophage infiltration between myocardiocytes and granulocyte accumulation within fibrotic tissue. This suggests a role of innate immunity in myocardial damage, in addition to lymphocyte activation (figure 5).
Conclusions This is one of the largest translational studies of ICI-myocarditis patients and matched controls. The preliminary data highlight the role of innate immunity, in addition to the previously known role of T lymphocytes. Advancing molecular understandings of ICI-myocarditis will allow us to design more targeted, effective immunosuppressive treatments for ICI-myocarditis.
Acknowledgements Laboratories of Dr Wilson Miller, Dr Sonia Del Rincón, Dr Réjean Lapointe, Dr Jun Ding, and Dr Lucas Salas.
Funding from Canadian Institutes of Health Research and a generous donation to the Jewish General Hospital Clinical Research Unit by Cathy Monticciolo-Cianci in memory of her mother Maria Monticciolo.
Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64.
Axelrod ML, Meijers WC, Screever EM, Qin J, Carroll MG, Sun X, et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature. 2022;611(7937):818–26.
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