Mast cells may hold the answer to ICS response in COPD

COPD

By Selina Wellbelove

25 Jan 2023

Th2 high and mast cell gene signatures have been identified as potential predictors of a response to corticosteroid treatment in patients with COPD.

An international team of researchers sought to determine whether gene expression signatures found in asthma patients could be used to identify a subgroup of COPD patients with steroid sensitivity.

The study, published in Thorax, revealed that certain sputum-derived transcriptomic signatures from an asthma cohort were associated with steroid sensitivity in patients with COPD, and were largely driven by mast cell associated genes.

The researchers undertook gene expression profiling in bronchial biopsies of 46 patients taking part in the GLUCOLD clinical trial, to determine the distribution and enrichment scores of three transcriptome-associated clusters (TAC) – a Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3).

After 30 months of treatment with inhaled corticosteroids (ICS) and a long-acting β-agonist (LABA), it was found that TAC1 had a significantly lower ES, while the Th2-low signatures remained unaffected.

Also, increased TAC1 expression was linked with higher sputum eosinophil counts, which according to the researchers was in line with prior findings “that asthma-derived Th2 signatures measured in bronchial biopsies correlate with airway wall eosinophil counts and blood eosinophil percentages and a more severe airflow obstruction in COPD”.

 “The TAC1 signature (high eosinophilia/Th2 high) was found to have variable expression across patients with COPD which serves to confirm the existence of an eosinophilic phenotype associated with the Th2 pathway in a subset of patients with COPD,” they wrote.

“In addition, the suppression of this signature by ICS therapy and the reversal of the expression of this signature by cessation of ICS therapy reinforces the similarity of this COPD endotype to severe eosinophilic asthma”.

The investigators also found that the ICS treatment affect on TAC1 was largely due to three genes expressed in mast cells: TPSB2, IL1RL1 and CPA3 (carboxypeptidase A3).

Taken together, the data show that the Th2-high TAC1 signature was linked to ICS responsiveness in COPD, and “could predict the degree of suppression of mast cell inflammation following ICS treatment”, the authors concluded.

Asthma-derived signatures such as the TACs may be a useful tool to identify patients with COPD that have asthma-like features such as responsiveness to ICS therapy, Th2-directed or mast cell-directed treatments, they added.

Mast cells as ICS targets

Writing in a linked editorial Dr Andrew Higham, Division of Immunology, Immunity to Infection and Respiratory Medicine, and Professor Dave Singh, Medicines Evaluation Unit, both at Manchester University NHS Foundation Trust, said that while the findings of the current study were not definitive there was clinical evidence to suggest a reduction in bronchial biopsy mast cell numbers with ICS treatment in COPD.

Furthermore, they noted that both MCT and MCTC numbers were lower in the bronchial biopsies of COPD ICS users versus non-users, with reduced mast cell gene expression in ICS users.

“While closely studied in asthma, the role of these cells in COPD has been largely ignored. Mast cells may hold the answer to understanding ICS responses in COPD,” they concluded.

Already a member?

Login to keep reading.

OR
Email me a login link