IdeNtifying reSponse defIninG mecHanisms for biological TherapieS in SevereAsthma (INSIGHTS ); assessing the role of CD4-CTLs

San Diego Biomedical Research Institute, San Diego CA

Investigators

Abstract

PROJECT SUMMARY Severe asthma, characterized by persistent airway inflammation and corticosteroid resistance, afflicts millions of Americans with limited therapeutic options. Clinicians currently rely on Type 2 immune biomarkers for patient classification (T2HIGH vs. T2LOW) and treatment decisions. However, real-world studies revealed the over- representation of the T2HIGH endotype in severe asthma and those treated with anti-T2 biologic therapies exhibit contrasting responses, challenging the efficacy of this T2 dichotomy and highlighting the need to explore alternative pathophysiological drivers. Our single-cell transcriptome analysis of T cells from inflamed airways in severe asthmatics identified a novel subset of pathogenic airway tissue resident cytotoxic CD4+ T cells (CD4-CTLs). Despite biologic treatment, CD4- CTLs remained activated, producing inflammatory molecules. Cell proportions analysis linked CD4-CTLs to asthma severity and lung function impairment, particularly in males with late-onset asthma. The study strongly supports CD4-CTLs' significant contribution to airway inflammation, potentially hindering T2-biologic response. Led by a multidisciplinary team of experts in clinical asthma, and immuno-genomics, Drs. Kurukulaaratchy and Seumois, our INSIGHTS study aims to assess the impact of CD4-CTLs on severe asthma pathogenesis and T2- biologics response at a larger scale. AIM 1: We will analyze airway CD4-CTLs from blood and sputum samples collected from 160 severe asthmatic patients before, and 12- and 24- months after initiating T2-biologic therapy. We will evaluate the impact of CD4- CTLs on T2-biologics response through extensive clinical analysis. Samples will be collected by three clinical centers [University of Southampton, UK; University of Michigan, Ann Arbor, US, and University of California, San Diego, US] establishing the clinical significance of CD4-CTL as a new player in asthma pathogenesis. AIM 2: With the planned collection of samples, we will generate up to 1 million single-CD4-CTL cell transcriptomes allowing us to comprehensively decipher the pathogenic cellular and molecular features of CD4- CTLs in asthma severity and response to T2-biologics, as well as investigate their function through TCR- reactivity and interactions with structural cells analysis. In summary, this unique translational proposal aims to unveil mechanisms causing a lack or loss of response to T2-biologics in severe asthma, focusing on CD4-CTLs. Findings could establish CD4-CTLs as a better predictor for patient stratification, leading to novel therapies for unmet patient needs.