Macrophage CCL18 promotes lung inflammation in checkpoint inhibitor pneumonitis

作者：Mohammad I. Ghanbar, A.F. Villabona-Rueda, Nicolas Philip, Romy Rodriguez Ortega, Shannon Fonti, Arabellis Wally, Haiyang Jiang, Rulin Wang, Wilhelm Berger, Jeffrey Thiboutot, Hans C. Lee, Patrick M. Forde, Jarushka Naidoo, Julie R. Brahmer, Sang Taek Kim, Naval Daver, Mehmet Altan, Ajay Seshadri, Pierre Van Mol, Els Wauters, François‐Xavier Danlos, Jérôme Le Pavec, Ariane Laparra, Rachel L. Damico, Srinivasan Yegnasubramanian, Sonye K. Danoff, Franco R. D’Alessio, Karthik Suresh · 发表于：American Journal of Respiratory Cell and Molecular Biology · 年份：2025 · DOI：10.1165/rcmb.2025-0405oc · 被引用次数：4 · 研究领域：Cancer Mechanisms and Therapy、Pharmacological Receptor Mechanisms and Effects、Peptidase Inhibition and Analysis

BACKGROUND: 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. OBJECTIVE/METHODS: To investigate the mechanisms underlying alveolar inflammation in patients with CIP, human bronchoalveolar lavage fluid (BALF) samples from control patients and patients with CIP 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. RESULTS: Analysis of scRNA-seq and flow cytometry data demonstrated increased macrophages in patients with CIP compared to controls. Several distinct proinflammatory alveolar macrophage subsets were increased in CIP. CIP macrophages expressed increased CCL18 at the transcript (scRNA-seq), cellular (flow cytometry) and secreted protein (BALF ELISA) levels. BALF CCL18 levels were associated with clinical CIP severity. CCL18 overexpression in mice promoted lung inflammation that phenocopied human CIP, including upregulation of proinflammatory macrophage subsets. CONCLUSION: These findings suggest that BALF macrophages and CCL18 protein levels are increased in patients with CIP and associate with gre...