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Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma, a disease characterized by malignant T cells that home to the skin. In early stages, clinical presentation is often indistinguishable from benign chronic inflammatory skin diseases such as atopic dermatitis (AD), posing a challenge for proper diagnosis and treatment. Previous studies have established that MF is characterized by the expansion of a single T-cell clone, whereas benign skin conditions are polyclonal in nature. In this study, we aimed to use single-cell RNA sequencing data to detect distinct transcriptomic features of early-stage MF in comparison to AD skin. In early-stage MF, we observed gene expression differences in cells of both the stroma and the immune system, with keratinocytes exhibiting increased interferon response and proliferation (STAT1, ICAM1, HLA-DRA, GJB2), while fibroblasts displayed tumour-associated programs (CXCL2, TNFAIP6, CEBPD). Myeloid cells exhibited expression of immunomodulatory genes (RUNX3, DDIT4, IL4I1), and malignant T-cells expressed exhaustion-associated markers (CXCL13, SOCS3, F2R, ETV1), as opposed to AD and healthy control samples. Thus, our results provide a novel insight into the immune-stroma crosstalk in the tissue microenvironment of early-stage MF vs. AD skin lesions.