CXCR6⁺ T Cells Drive Immune Checkpoint Inhibitor Myocarditis.

Area of Science:

• Immunology
• Cardiology
• Pharmacology

Background:

• Myocarditis is a serious complication of immune checkpoint inhibitors (ICIs).
• Combination ICI therapy, particularly with anti-LAG-3 and anti-PD-1, elevates myocarditis risk.
• The specific T-cell populations and signaling pathways driving cardiac infiltration in ICI myocarditis remain unclear.

Purpose of the Study:

• To investigate the risk of myocarditis associated with anti-LAG-3 combination therapy.
• To elucidate the mechanisms of T-cell driven cardiac inflammation in anti-LAG-3/PD-1 therapy-induced myocarditis.
• To identify potential therapeutic targets for ICI myocarditis.

Main Methods:

• Utilized VigiBase pharmacovigilance data to assess myocarditis risk with anti-LAG-3 treatments.
• Developed and analyzed a mouse model (Lag3-/-, Pdcd1-/-) for ICI myocarditis.
• Employed histology, flow cytometry, ECG, single-cell RNA sequencing, and antibody depletion for cardiac phenotyping.

Main Results:

• Confirmed increased myocarditis risk with anti-LAG-3 combination therapy.
• Observed severe cardiac inflammation, arrhythmias, and premature death in the mouse model.
• Identified CXCR6 as a marker for pathogenic cardiac T cells and CXCL16 on macrophages, with anti-CXCR6 therapy mitigating disease severity.

Conclusions:

• ICI myocarditis is driven by an expansion of CXCR6+ T cells.
• CXCR6+ T cells are critical for the pathogenesis of ICI myocarditis.
• CXCR6 represents a promising therapeutic target for managing ICI-induced myocarditis.