Macrophage CCL18 Promotes Lung Inflammation in Checkpoint Inhibitor Pneumonitis.

Summary

Multi-omic profiling of BALF from patients with checkpoint inhibitor pneumonitis revealed expansion of pro-inflammatory alveolar macrophage subsets with marked upregulation of CCL18, which correlated with clinical severity. In vivo CCL18 overexpression in mice phenocopied human CIP with enhanced lung inflammation, implicating CCL18 as a causal mediator and potential biomarker/therapeutic target.

Key Findings

• CIP patients showed increased alveolar macrophages with multiple pro-inflammatory subsets by scRNA-seq and flow cytometry.
• CCL18 expression (transcript, cellular, and BALF protein) was elevated in CIP and associated with greater clinical severity.
• CCL18 overexpression in mice induced lung inflammation that phenocopied human CIP, including pro-inflammatory macrophage signatures.

Clinical Implications

BALF CCL18 could aid CIP risk stratification and monitoring; therapeutics targeting CCL18 or its signaling may mitigate CIP without broadly suppressing antitumor immunity.

Limitations

• Sample sizes and enrollment details are not fully specified; generalizability across tumor types requires confirmation
• Interventional blockade of CCL18 was not tested; murine overexpression may not recapitulate all human CIP features

Future Directions

Prospective studies validating BALF/serum CCL18 as a predictive biomarker and interventional trials targeting CCL18 signaling to prevent or treat CIP.