Spatial transcriptomics uncovers unique tumor microenvironments in folliculotropic versus classic mycosis fungoides

The most common subtype of cutaneous T-cell lymphoma, mycosis fungoides (MF), is characterized by proliferation of malignant T cells in the skin. In the more clinically aggressive folliculotropic MF (FMF), malignant T cells localize to follicular epithelium, whereas in classic MF, they infiltrate the dermis and epidermis. How the localization of neoplastic T cells to the follicular niche contributes to the clinical aggression in FMF is unclear. To uncover the tumor microenvironmental differences between perifollicular FMF and dermal classic MF regions, we analyzed patient samples using spatial transcriptomics. Transcripts were collected from specific cell subsets within follicular (FMF) and dermal (classic MF) regions of interest to compare gene expression, spatial deconvolution, and pathway activity. Our work revealed that the neoplastic CD4 T cells around the hair follicles in FMF had a highly inflammatory phenotype, better adaptation to cellular starvation, higher metabolic activity, and enhanced antigen presentation. In contrast, cutaneous T-cell lymphoma-associated macrophages in FMF exhibited an immunosuppressive phenotype with decreased IL-2 and IFN signaling. These findings suggest that the follicular microenvironment may provide survival advantages to malignant T cells while promoting a dysregulated antitumor immune response. These observations provide insight into the mechanisms underlying the more aggressive clinical features of FMF versus classic MF.