Genomic and spatial transcriptomics identify fibroblast-associated microenvironment in early mycosis fungoides progression.

Early-stage mycosis fungoides (MF) manifests as patch or plaque lesions, and cancer-associated fibroblasts (CAFs) may promote tumorigenesis and Th2-skewed microenvironment. This study aimed to investigate genomic and transcriptomic changes from patch to plaque MF and assess their prognostic significance in early-stage disease. Whole-genome sequencing, CosMx Spatial Molecular Imaging, a single-cell-resolution spatial transcriptome, and immunohistochemical staining for CAF markers FAP, TIMP-1, and CXCL12 were conducted. Whole-genome sequencing showed similar single-nucleotide, copy-number, and structural variants in patch and plaque lesions. Spatial transcriptomics identified fibroblasts as a key signaling cells in both lesion types, with plaque lesions exhibiting expanded fibroblast-driven communication networks, including greater interactions with B cells and enhanced T-cell chemotaxis. CXCL12 was markedly upregulated in fibroblasts from plaque-MF and correlated with collagen gene expression and CCL19, a key ligand mediating fibroblast-T-cell signaling. T cells in plaque lesions also displayed higher CXCL12 and CCL19 expression and lower expression of cytotoxicity-related genes. In the immunohistochemical cohort, high FAP and TIMP-1 expression correlated with poorer progression-free survival, whereas CXCL12 expression was associated only with progression to tumor-stage disease. In conclusion, this study identifies differences between patch and plaque MF and underscores the clinical and prognostic significance of CAFs in patients with early-stage disease.