A recent study published in Nature Communications has elucidated the impact of biologic therapies on the transcriptional profiles of circulating immune cells in patients with severe eosinophilic asthma. The research, employing single-cell RNA sequencing, reveals significant alterations in the states of various immune cell populations following treatment with either anti-IL-5 antibodies (mepolizumab, reslizumab) or an anti-IL-4Rα antibody (dupilumab). These findings offer valuable insights into the molecular mechanisms underlying the clinical benefits of these therapies.
Transcriptional Shifts in Immune Cell Subsets
The study, which included eight patients with severe eosinophilic asthma, tracked changes in clinical variables and immune cell transcriptomes over six months of biologic therapy. Four patients received mepolizumab or reslizumab, while the other four were treated with dupilumab. The analysis of over 89,000 cells revealed that while the overall proportions of T/NK, myeloid, and B cells remained relatively stable, the transcriptional states of cell subtypes were significantly altered.
Notably, classical monocytes (CMs) exhibited a shift from IL1B+ CMs to S100A+ CMs after six months of treatment, irrespective of the biologic agent used. Furthermore, the transcriptional profiles of CD4+ T cells showed considerable differences after six months, leading to their classification into distinct states (S0 and S1) representing different functional characteristics.
Downregulation of NF-κB Pathway
A key finding across multiple immune cell types was the downregulation of genes involved in the NF-κB pathway. This observation suggests a broad anti-inflammatory effect of biologic therapies in severe asthma, as the NF-κB pathway plays a central role in regulating inflammatory responses. Genes such as FOS, JUN, DUSP1, and NFKBIA, all critical components of the NF-κB signaling cascade, were commonly downregulated in T/NK cells, myeloid cells, and B cells.
Differential Effects of Biologics on CD4+ T Cells
Further analysis revealed distinct effects of dupilumab and mepolizumab/reslizumab on CD4+ T cell subtypes. Mepolizumab/reslizumab treatment was associated with a higher proportion of naïve S1 CD4+ T cells, while dupilumab treatment led to an enrichment of TCM S1 CD4+ T cells. These differences suggest that the two classes of biologics may exert their therapeutic effects through different mechanisms of action on T cell populations.
Connectivity mapping of cell-cell interactions also highlighted differences between the two treatment groups. Dupilumab had a greater impact on both the MHC-II signaling pathway network and the CD40 signaling pathway, with interactions between CD4+ T and B cells considerably decreasing only in patients treated with dupilumab.
Clinical Implications
These findings provide a deeper understanding of how biologic therapies modulate the immune system in severe eosinophilic asthma. By identifying specific transcriptional changes and differential effects of various biologics, this research may pave the way for more personalized treatment strategies tailored to individual patient profiles. The study underscores the power of single-cell RNA sequencing in dissecting the complex immunological mechanisms underlying asthma and in informing the development of novel therapeutic interventions.
