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

Early-stage mycosis fungoides manifests as patch or plaque lesions, and cancer-associated fibroblasts may promote tumorigenesis and a Th2-skewed microenvironment. This study aimed to investigate genomic and transcriptomic changes from patch to plaque mycosis fungoides 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 cancer-associated fibroblast markers FAP, tissue inhibitor of metalloproteinase-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 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 mycosis fungoides 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 tissue inhibitor of metalloproteinase-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 mycosis fungoides and underscores the clinical and prognostic significance of cancer-associated fibroblasts in patients with early-stage disease.