Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy, characterized by acute lung injury leading, in severe cases, to hypoxic respiratory failure and death. CIP incidence in lung cancer is high (10-15%). Yet, the pathophysiology of CIP is poorly understood. To investigate the mechanisms underlying alveolar inflammation in patients with CIP, human bronchoalveolar fluid (BALF) samples from control and CIP patients were analyzed using flow cytometry, single cell RNA sequencing (scRNA seq), and ELISA. Findings were validated using multiple external cohorts. In vitro experiments and in vivo rodent models were employed to investigate the mechanisms driving alveolar inflammation in CIP. Analysis of scRNA seq and flow cytometry data demonstrated increased macrophages in patients with CIP compared to controls. Several distinct pro-inflammatory alveolar macrophage subsets were increased in CIP. CIP macrophages expressed increased chemokine ligand-18 (CCL18) at the transcript (scRNAseq), cellular (flow cytometry) and secreted protein (BALF ELISA) level. BALF CCL18 levels were associated with clinical CIP severity. CCL18 over-expression in mice promoted lung inflammation that phenocopied human CIP, including upregulation of pro-inflammatory macrophage subsets. These findings suggest that BALF macrophages and CCL18 protein levels are increased in patients with CIP and associate with greater CIP severity. Additionally, CCL18 promotes lung inflammation in mice that mimics human CIP, suggesting a causal role for CCL18 in CIP.
Ghanbar et al. (2025) studied this question.