Track: Basic Science

Abstract:

Fibroblasts can undergo functional reprogramming into cancer-associated fibroblasts (CAFs), which promote tumor growth, modulate immune response, and remodel the extracellular matrix (ECM). Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, fibroblasts interact with malignant T cells, immune infiltrates, and vasculature within a complex tumor microenvironment. Recent single-cell RNA sequencing (scRNA-seq) studies reveal that fibroblasts in MF range from quiescent normal fibroblasts (NFs) to activated CAF subsets with distinct cytokine, matrix, and contractility signatures. Notably, CAFs are also detected in non-lesional MF skin, suggesting early microenvironmental changes. We integrated scRNA-seq datasets from 27 skin biopsies including healthy controls and MF patients at early, follow-up, lesional, and non-lesional stages. Fibroblasts were classified as NF or CAF based on an NF gene signature. CAFs were further subdivided into progenitor (pCAF), inflammatory (iCAF), matrix-producing (matCAF), and myofibroblastic (myoCAF) subtypes. CAF composition shifted across disease stages. Early MF was enriched in iCAFs (~36%) and myoCAFs (~19%), with matCAFs (~33%). Follow-up samples showed matCAF predominance (~57%) and reduced iCAFs (~25%), indicating ECM remodeling even outside lesions. Lesional MF displayed mixed profile of matCAF (~45%) and myoCAF (~19%), with moderate iCAF (~28%), reflecting concurrent fibrotic and contractile remodeling. Non-lesional skin was similarly matCAF-rich (~54%) with iCAFs (~26%). pCAFs remained rare (<1.2%) across all conditions. Unclassified CAFs decreased from ~12% in early MF to ~3–7% later. These findings support a model in which early MF is driven by inflammation-associated fibroblast activation, progressing to ECM-dense remodeling in subclinical skin, culminating in combined fibrotic and contractile remodeling in overt lesions.

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Joshua Levy