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Clonal CD8 T cells orchestrate arrhythmogenic inflammation in immune checkpoint inhibitor-associated myocarditis

ABSTRACT: Objective: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are frequently associated with immune-related adverse events, particularly in combination regimens. ICI-associated myocarditis (ICI-M) is rare but highly lethal, with a mortality rate approaching 50% and a notable risk of fatal ventricular arrhythmias. Prevention and effective management of ICI-M remain significant clinical challenges. This study aims to elucidate the immune landscape and spatial organization of immune cells in ICI-M using single-cell multi-omics in a preclinical mouse model. Methods: We utilized Ctla4+/–Pdcd1–/– mice, modeling human ICI-induced myocarditis. Single-cell RNA (scRNAseq) and T cell receptor (TCR) sequencing were performed on heart-infiltrating immune cells and peripheral blood mononuclear cells (PBMCs). Spatial transcriptomics was applied to map immune infiltration in cardiac tissue. Results: Approximately half of Ctla4+/–Pdcd1–/– mice died after 100 days, while Ctla4+/+ mice showed normal survival. ECG monitoring identified ventricular arrhythmias in 15% of Ctla4+/–Pdcd1–/– mice. Histology revealed severe myocardial inflammation and fibrosis. Cardiac scRNAseq data indicated that T cells were the predominant immune population in ICI-M hearts. TCR sequencing demonstrated substantial overlap in TCR clonotypes between cardiac-infiltrating and circulating CD8+ T cells. These TCR-shared CD8+ T cells exhibited an activated phenotype and were enriched in pathways associated with allograft rejection and inflammation. Spatial mapping revealed localization near the AV node and subendocardium, implicating potential CD8+ T cell–mediated conduction disruption. Conclusion: Clonal, activated CD8+ T cells contribute to arrhythmogenic myocarditis in ICI-M. Targeting specific TCR-peptide-MHC interactions may enable myocarditis prevention without impairing antitumor efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE299032 | GEO | 2025/06/11

REPOSITORIES: GEO

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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.

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Clonal CD8 T cells orchestrate arrhythmogenic inflammation in immune checkpoint inhibitor-associated myocarditis

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