Towards the role of the skin microbiome in the aetiopathogenesis of cutaneous T-Cell Lymphoma

Abstract

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of non-Hodgkin lymphomas with primary skin involvement. Its aetiopathogenesis remains incompletely understood, partly due to pronounced clinical and transcriptional heterogeneity. This cumulative dissertation presents a multi-omics investigation into the role of the skin microbiome in MF pathobiology, encompassing metagenomic, transcriptomic, virologic, and T-cell receptor (TCR) sequencing data from patient-matched lesional and nonlesional skin. In addition, functional assays were performed on patient-derived skin isolates.

Publication 1 reviews the interplay between transcriptional heterogeneity and the skin microbiota in CTCL, proposing a reciprocal relationship between neoplastic T-cell signalling and microbial colonisation.

Publication 2 provides the first conclusive evidence for taxonomic and functional microbiome shifts on MF skin. It identifies a distinct subgroup of patients (ΔSA-positive) with increased lesional abundance of Staphylococcus aureus, reduced microbial diversity, a restricted TCR repertoire, and inferior clinical outcome. Lesional isolates of ΔSA-positive S. aureus exhibited resistance to cutaneous antimicrobial peptides, which were ectopically expressed and may have contributed to commensal flora eradication. This strain also harboured mutant spa, a virulence factor known to activate NF-κB signalling, thereby supporting a functional role in disease progression.

Publication 3 shows that transcriptional heterogeneity may reflect differences in T-cell signalling activity. Multi-omic data integration revealed ΔSA-positive S. aureus strain-driven activation of non-canonical NF-κB and IL-1β signalling, both implicated in T-cell activation and MF progression. Importantly, denoising the skin transcriptome from microbial influence resolved the observed differential expression pattern. Additionally, antiviral signatures and Epstein–Barr virus reactivity in blood and skin suggest a two-hit model of MF aetiopathogenesis involving viral and bacterial triggers.

Together, this thesis positions the skin microbiome as a clinically relevant modulator of MF biology. The findings support S. aureus as a potential prognostic biomarker and therapeutic target and lay the groundwork for microbiome-informed precision medicine.