Researchers have discovered that blocking the exhaustion marker programmed cell death protein 1 (PD-1) on the airway leucocytes of patients with cystic fibrosis (CF) improves the killing of bacteria, as published in the Journal of Cystic Fibrosis

Studies have demonstrated that macrophages play a crucial role in tissue homeostasis and injury response. In patients with CF, airway macrophages demonstrate mutations that make them defective. In addition, mucin hyperconcentration and dehydration hamper their immune regulatory function.

“[PD-1] is an immune checkpoint protein that regulates cell behavior during immune responses, with best known functions related to T-cell control in cancer and viral infection,” the authors of the study wrote.

PD-1 has been demonstrated to impede the function of macrophages, reducing their role in clearing bacteria during airway inflammation. The researchers hypothesized that the blocking of the PD-1 pathway may enhance bacteria killing in patients with CF and improve clinical outcomes. 

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The researchers obtained immune cells from blood and bronchoalveolar lavage fluid from 45 pediatric patients with CF. The presence of the PD-1 signaling pathway was determined through flow cytometry. The research team discovered that PD-1 was expressed on airway macrophages higher than they were on airway neutrophils and T cells.

The researchers discovered that in a subgroup of 24 participants, PD-1 expression on airway macrophages correlated with structural lung damage and bronchiectasis. In addition, PD-1 expression was negatively correlated with the amount of macrophages. PD-1 expression was also in part linked to early neutrophilic inflammation that decreased the immune response’s ability to kill bacteria, opening the pathway for chronic airway disease often seen in patients with CF.

“We showed preliminary evidence that PD-1 blockade in airway leukocytes improved bacterial clearance,” the authors concluded.

Reference

Margaroli C, Horati H, Garratt LW, et al. Macrophage PD-1 associates with neutrophilia and reduced bacterial killing in early cystic fibrosis airway diseaseJ Cyst Fibros. 2022;S1569-1993(22)00588-4. doi:10.1016/j.jcf.2022.06.001