Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor

Immune checkpoint inhibitors (ICIs) are widely used in anti-cancer therapies, but they can cause morbid and potentially fatal immune-related adverse events (irAEs), such as ICI-related myocarditis (irMyocarditis). The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define immune responses in heart, tumor, and blood in irMyocarditis patients and controls by leveraging single‐cell RNA sequencing (scRNA‐seq) coupled with T-cell Receptor Sequencing (TCR-Seq). Our analysis demonstrated increased frequencies of cytotoxic T cells, inflammatory mononuclear phagocytes (MNPs), conventional dendritic cells (cDCs), and inflammatory fibroblasts in irMyocarditis heart tissue. Additionally, we revealed decreased frequencies of plasmacytoid dendritic cells, cDCs, and B lineage cells but an increased frequency of MNPs in the blood of irMyocarditis patients. Raw data for heart and blood can be found in dbGaP. All processed data and raw TCRseq data from heart tissue and tumor samples for this study can be found in GEO (Accession number GSE228597).Subject IDs with the prefix "SIC" were collected by the Severe Immunotherapy Complications (SIC) service at MGH due to suspicion of immune-related adverse events. Subject IDs with the prefix "donor" were collected by the MGH Melanoma Biobank at scheduled timepoints; this biobank systematically collects samples from patients at MGH at clinically relevant timepoints. ]]>
Inclusion CriteriaCase: Patients were included if they had cancer which had been treated with an immune checkpoint inhibitor and if they or their designated healthcare proxy provided informed consent. irMyocarditis heart tissue and blood were from patients diagnosed with immune checkpoint inhibitor-associated myocarditis by MRI, biopsy, or autopsy as part of routine clinical care. Control: Control heart tissue was from patients that had a biopsy or autopsy without findings of myocarditis. Control PBMC samples were from patients who had received at least two doses of an ICI regimen that contained a PD-1 inhibitor and had at least 8 weeks of follow-up before next therapy or death. Patients were included if they had no documented irAEs on that line of therapy. ]]>