T-cell plasticity mediating treatment resistance and side effects in atopic dermatitis

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY Type 2 inflammation is mediated by a specific branch of the immune system, assumed to have developed as a major defense mechanism against parasitic infections and infestations. However, in our modern lifestyle, this kind of immune axis is mostly encountered in the context of pathological activation, especially in inflammatory diseases such as atopic dermatitis (AD). Consistently, the type 2 blocking antibody dupilumab was the first targeted FDA-approved treatment for AD. However, only 50% of patients achieved a 75% improvement in their skin scores upon dupilumab treatment during phase III clinical trials, and 10% even develop de novo paradoxical inflammatory side effects such as blepharitis, conjunctivitis, psoriasiform rashes, or a specific form of dupilumab- associated head/neck dermatitis (DAHND). Until today, mechanisms underlying treatment resistance and paradoxical inflammatory side effects of dupilumab treatment remain only insufficiently understood. Thus, there is an urgent need to correct this knowledge gap for the development of better treatment modalities for AD. Preliminary data from our group show increases in type 1 and type 22 immune signatures in dupilumab non- responders at baseline and throughout treatment. In addition, we find oligoclonal expansion of cytotoxic type 22 T cells in biopsies of DAHND. Interestingly, these cells showed overlapping features with type 2 cells, suggesting a considerable degree of inflammatory T cell plasticity, or transdifferentiation, both in dupilumab-resistant AD and in DAHND. In this proposal, we will utilize human skin biopsies from dupilumab-treated AD patients to study cellular and molecular features of the immune microenvironment in resolving (dupilumab responders), stable (dupilumab non-responders) and paradoxically flaring skin lesions (DAHND and psoriasiform rashes) through high-throughput techniques including single-cell RNA-seq, single-cell ATAC, and spatial transcriptomics. T cells isolated from these lesions will be studied in in vitro cultures and in skin spheroid models to better characterize their cytokine production behavior over time, as well as their crosstalk with cells of the tissue microenvironment, respectively. The rationale for this proposal is that once it is understood how type 2 cells are regulated in AD during individual treatment responses, these mechanisms can be utilized to create effective and novel stratified therapies for AD.