Single-cell RNA sequencing reveals transcriptional changes in circulating immune cells from patients with severe asthma induced by biologics

Abstract

Patients with severe eosinophilic asthma often require systemic medication, including corticosteroids and anti-type 2 (T2) cytokine biologics, to control the disease. While anti-IL5 and anti-IL4Rα antibodies suppress the effects of IL-4, IL-5 and IL-13, the molecular pathways modified by these biologics that are associated with clinical improvement remain unclear. Therefore, we aimed to describe the effects of T2-targeting biologics on the gene expression of blood immune cells. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from eight patients with severe eosinophilic asthma treated with mepolizumab, reslizumab, or dupilumab. PBMCs were obtained before the initiation of biologics and at 1- and 6-month timepoints after the initiation of treatment to elucidate treatment-induced changes. During treatment, the proportions of T cells/natural killer (NK) cells, myeloid cells, and B cells did not change. However, the composition of classical monocytes (CMs) changed: IL1B+ CMs were reduced, and S100A+ CMs were increased. The subsets of T cells also changed, and significant downregulation of the NF-κB pathway was observed. The genes related to the NF-κB pathway were suppressed across T/NK, myeloid, and B cells. The transcriptional landscape did not significantly change after the first month of treatment, but marked changes occurred at six-month intervals. In conclusion, regardless of the type of biologics used, suppression of T2-mediated pathways ultimately reduces the expression of genes related to NF-κB signaling in circulating immune cells. Further studies are warranted to identify potential biomarkers related to treatment response and long-term outcomes. Clinical trial registration number: NCT05164939 Severe asthma is a chronic disease where the airways are inflamed, causing breathing issues even with high-dose inhaled corticosteroids. Current treatments, including biologics, help but don’t fully control the disease. Researchers studied how biologics affect immune cells in severe asthma patients. In this study, they analyzed blood samples from eight patients treated with biologics like mepolizumab, reslizumab, and dupilumab. They used single-cell RNA sequencingto examine changes in gene expression in immune cells over six months. The researchers found that biologics reduced inflammation by altering specific immune cell pathways. They observed a decrease in pro-inflammatory genes and an incrḍease in genes related to immune regulation. These changes suggest that biologics help control severe asthma by modifying immune cell behavior. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.