Introduction:
Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF). Malignant FMF T-cells localize to the pilosebaceous unit while malignant T-cells in classic MF (CMF) infiltrate the dermis and epidermis. How the follicular niche contributes to the clinical aggression in FMF is unclear.
Objectives:
To compare the gene expression signatures in the perifollicular regions of FMF (FMF-F) versus dermal regions of CMF (CMF-D) using spatial transcriptomics on patient samples.
Methods:
Regions of interest (ROIs) were selected in FMF-F and CMF-D biopsy specimens. Using NanoString GeoMx, transcriptomic data were collected from specific cell subsets (CD4+, CD68+, CD8+) within the entire ROIs. Spatial deconvolution, differential gene expression, bulk pathway analysis, and single sample GSEA (ssGSEA) were performed.
Results:
Leukocyte activation and cellular transport genes were upregulated in FMF-F compared to CMF-D, and inflammatory genes were downregulated in FMF-F macrophages. In bulk analysis, antigen presentation and inflammatory pathways were upregulated in FMF-F, while FMF-F macrophages showed downregulation of inflammation. Metabolic pathways (carbohydrates, amino acids) were significantly upregulated in FMF-F CD4+ T-cells. ssGSEA revealed decreased IL-7 signaling and increased IL-10 signaling in FMF-F ROIs. Finally, the cellular response to starvation, cholesterol efflux, and metabolism of amino acids and glycoproteins were upregulated in FMF-F CD4+ T-cells.
Conclusions:
FMF CD4+ T-cells exhibit a higher inflammatory phenotype, more antigen presentation activity, and higher response to starvation. In contrast, FMF-F macrophages exhibit a less inflammatory profile, supporting a dysregulated antitumor immune response. These findings may help explain the pathogenesis driving the aggressive phenotype seen in FMF compared to CMF.
