Dataset Information

An Interferon-γ-Driven Myeloid Inflammatory Signature defines Glucocorticoid-Resistance of Immune Checkpoint Inhibitor-Associated Myocarditis

ABSTRACT: Immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis) is a rare but severe immune-related adverse event characterized by myocardial inflammation and injury. Although high-dose glucocorticoids represent first-line therapy, a subset of patients exhibits persistent myocardial injury despite treatment. In this study, we analyzed a cohort of 74 patients with ICI-myocarditis and classified patients based on longitudinal high-sensitivity cardiac troponin T (hs-cTnT) trajectories following glucocorticoid initiation into glucocorticoid-sensitive (GC-S) and glucocorticoid-refractory (GC-R) groups. Clinical outcomes, including major adverse cardiac events (MACE), were assessed. To investigate underlying biological differences, single-nucleus RNA sequencing (snRNA-seq) was performed on endomyocardial biopsy samples from GC-S (n=2) and GC-R (n=4) patients. The dataset provides high-resolution transcriptional profiles of myocardial cell populations, enabling analysis of cellular composition and inflammatory signaling pathways associated with differential treatment response. This resource supports investigation of immune cell heterogeneity and transcriptional programs in ICI-myocarditis, with a focus on differences between glucocorticoid-sensitive and glucocorticoid-refractory disease states.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329991 | GEO | 2026/05/09

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathophysiologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. We observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) were found selectively in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8+T-cells and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.

Dataset Information

An Interferon-γ-Driven Myeloid Inflammatory Signature defines Glucocorticoid-Resistance of Immune Checkpoint Inhibitor-Associated Myocarditis

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets