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.

Cutaneous T-Cell Lymphomas (CTCL) presents with substantial clinical variability and transcriptional heterogeneity. In the recent years, several studies paved the way to elucidate aetiology and pathogenesis of CTCL using sequencing methods. Several T-cell subtypes were suggested as the source of disease thereby explaining clinical and transcriptional heterogeneity of CTCL entities. Several differentially expressed pathways could explain disease progression. However, exogenous triggers in the skin microenvironment also seem to affect CTCL status. Especially Staphylococcus aureus was shown to contribute to disease progression. Only little is known about the complex microbiome patterns involved in CTCL and how microbial shifts might impact this malignancy. Nevertheless, first hints indicate that the microbiome might at least in part explain transcriptional heterogeneity and that microbial approaches could serve in diagnosis and prognosis. Shaping the microbiome could be a treatment option to maintain stable disease. Here, we review current knowledge of transcriptional heterogeneity of and microbial influences on CTCL. We discuss potential benefits of microbial applications and microbial directed therapies to aid patients with CTCL burden.

We prove the Shafarevich conjecture for Fano threefolds of Picard rank 1, index 1 and degree 4.

We prove finiteness results on integral points on complements of large divisors in projective varieties over finitely generated fields of characteristic zero. To do so, we prove a function field analogue of arithmetic finiteness results of Corvaja-Zannier and Levin using Wang's function field Subspace Theorem. We then use a method of Evertse-Győry for concluding finiteness of integral points over finitely generated fields from known finiteness results over number fields.