The Skin Microbiome Stratifies Patients with Cutaneous T Cell Lymphoma and Determines Event-Free Survival

Abstract

Abstract Background: Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas that are characterized by the presence of clonal malignant T cells in the skin, with Mycosis fungoides (MF) being the most common entity. The role of the skin microbiome for MF development and progression are currently poorly understood. Methods: We used shotgun metagenomic profiling, real-time qPCR and T cell receptor sequencing to compare lesional and nonlesional skin of 20 patients with early and advanced MF that were treated at two independent German skin cancer centres. Additionally, Staphylococcus aureus and other bacterial species were isolated from MF skin for functional profiling and to investigate the S. aureus virulence factor spa. Results: We identified a subgroup of MF patients that exhibited a substantial dysbiosis on MF lesions with concomitant outgrowth of S. aureuson plaque while the other MF patients presented with a balanced microbiome on lesional skin. Dysbiosis and S. aureus outgrowth were accompanied with ectopic levels of cutaneous antimicrobial peptides (AMPs) and increased adaptation of the outgrowing, plaque-derived S. aureus strains, which may have resulted in or contributed to these microbiome perturbations. Furthermore, the plaque-derived S. aureus strains showed a reduced susceptibility towards antibiotics and an upregulation of the virulence factor spa, which also exhibited a potential gain-of-function mutation, that may render it highly potent to activate the NF-κB pathway. Last, we observed a restricted T cell receptor repertoire and a reduced event-free survival in patients with dysbiosis on MF lesions. Conclusions: Our data suggest that virulent, outgrowing S. aureus strains fuel pathogenesis in the MF patient subgroup with dysbiosis, possibly via highly potent spa that activates the NF-κB pathway. We therefore provide a solid basis for the role of the skin microbiome for MF progression and pave the way for potential microbiome modulating treatments specifically targeting S. aureus to prevent MF disease progression.