Single-Cell Analysis Reclassifies Eczematous Mycosis Fungoides as Severe Atopic Dermatitis 2259810

Abstract Introduction Mycosis fungoides (MF), the prevalent subtype of cutaneous T-cell lymphoma (CTCL), primarily affects the skin and progresses systemically over time. Early-stage MF diagnosis relies on immunohistochemistry, T cell receptor (TCR) gene rearrangement testing, and clinical evaluation. However, in the clinic settings, we observe eczematous MF (eMF) patients who meet early-stage MF diagnostic criteria but exhibit phenotypes resembling atopic dermatitis (AD), and refractory to dupilumab. This study investigates the molecular characteristics of eMF in comparison to AD and classic MF, providing insights into its distinct pathophysiology and potential therapeutic implications. Methods Skin biopsies were collected from seven AD patients and eleven eMF patients. Paired single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) were conducted to evaluate transcriptional profiles and T-cell clonality. Publicly available MF and AD scRNA-seq data were used for comparative analysis. In addition, spatial transcriptomic profiling was performed to validate. Results Comparative transcriptomic analysis showed that the molecular profiles of T cells in eMF resembled those in AD rather than in conventional MF. Furthermore, in eMF, we observed oligoclonal T-cell expansions, which were not found in conventional MF both in scRNA-seq and spatial transcriptomic data. These expanded cells were predominantly Th22 cells, identified as the primary producers of IL-13, a key cytokine in AD pathophysiology. Conclusion eMF diagnostic phenotype resembles conventional MF, and AD primarily due to the hyperproliferation of Th22 cells and their expression of IL-13. In this context, this mechanism underscores the superior efficacy of Upadacitinib, which could target Th22 differentiation, over Dupilumab. As a result, our findings indicate that eMF is not cancer, but a Th22-mediated AD endotype. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)