Deciphering pathogenic cellular module at single-cell resolution in checkpoint inhibitor-related pneumonitis

Area of Science:

• Immunology
• Oncology
• Pulmonology

Background:

• Checkpoint inhibitor pneumonitis (CIP) is a severe immune-related adverse event.
• Its underlying pathophysiology is not well understood, hindering diagnosis and treatment.
• Identifying key cellular and molecular factors is crucial for managing CIP.

Purpose of the Study:

• To dissect the immunological complexity of CIP using single-cell transcriptome analysis.
• To identify cellular players and molecular pathways involved in CIP pathogenesis.
• To develop a diagnostic immune signature for CIP.

Main Methods:

• Single-cell transcriptome analysis of bronchoalveolar lavage fluid (BALF).
• T-cell receptor (TCR) repertoire analysis and pseudotime trajectory inference.
• Intercellular crosstalk analysis and immune signature development.

Main Results:

• CIP is associated with increased CXCL13+ T cells and hyperinflammatory CXCL9+ monocytes.
• CXCL13+ T cells show expanded TCR clonotypes and differentiate towards cytotoxic effectors.
• Monocyte-derived dendritic cells (DCs) may migrate to BALF, while anti-inflammatory macrophage differentiation is impaired.
• Activated pathways include CXCL9/10/11-CXCR3, FASLG-FAS, and IFNGR1/2-IFNG.
• A novel immune signature demonstrated diagnostic power (AUC=0.755) for distinguishing CIP+ from CIP- samples.

Conclusions:

• Single-cell analysis reveals key cellular players and pathways in CIP.
• CXCL13+ T cells and CXCL9+ monocytes are critical in CIP pathogenesis.
• The identified immune signature aids in CIP diagnosis.