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

Area of Science:

• Immunology
• Oncology
• Cardiology

Background:

• Immune checkpoint inhibitors (ICIs) are crucial cancer therapies but can trigger severe immune-related adverse events (irAEs).
• ICI-related myocarditis (irMyocarditis) is a rare but highly fatal irAE with poorly understood mechanisms and links to anti-tumor immunity.

Approach:

• Utilized single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing on heart and blood samples from 28 irMyocarditis patients and 23 controls.
• Integrated microscopy and proteomics to comprehensively analyze immune responses.
• Examined immune cell populations, transcriptional programs, and TCR clonality in affected tissues and circulation.

Key Points:

• Identified enriched populations of cytotoxic T cells, inflammatory macrophages, conventional dendritic cells (cDCs), and fibroblasts in irMyocarditis heart tissue.
• Discovered upregulated pro-inflammatory transcriptional programs across multiple cell types in the heart.
• Observed distinct T cell receptor (TCR) repertoires in heart and tumor tissues, indicating compartmentalized immune responses.
• Identified cardiac-expanded TCRs within a circulating, cycling CD8 T cell population as a novel peripheral biomarker associated with fatality.

Conclusions:

• Elucidated critical biological mechanisms underlying irMyocarditis pathogenesis.
• Highlighted potential therapeutic targets and identified a novel peripheral biomarker for predicting fatal outcomes.
• Advanced understanding of the complex interplay between anti-tumor immunity and immune-related adverse events.