Multiomic Data Integration Reveals Microbial Drivers of Aetiopathogenesis in Mycosis Fungoides

Abstract

BackgroundMycosis fungoides (MF) represents the most prevalent entity of cutaneous T cell lymphoma (CTCL). The MF aetiopathogenesis is incompletely understood, due to strong transcriptomic heterogeneity and opposing perspectives on the initial oncologic transformation mapping the event to both early thymocytes and mature, effector memory T cells. Recently, using clinical specimen, our group showed that the skin microbiome aggravates disease course, mainly driven by an outgrowing, pathogenic S. aureus strain carrying the virulence factor spa, which reportedly activates the T cell signalling pathway NF-{kappa}B. MethodsTo further investigate the role of the skin microbiome in MF aetiopathogenesis, we here performed RNA sequencing, multiomic data integration of the skin microbiome and skin transcriptome using Multi-Omic Factor Analysis (MOFA), virome profiling, and T cell receptor (TCR) sequencing in 10 MF patients representing a subset of our previous study cohort. ResultsWe observed that inter-patient transcriptional heterogeneity may be largely driven by differential activation of T cell signalling pathways. Strikingly, the MOFA model resolved the heterogenous activation pattern of T cell signalling after denoising the transcriptome from microbial influence. The MOFA model showed that the outgrowing S. aureus strain evoked signalling by non-canonical NF-{kappa}B and IL-1B, which likely fuelled the aggravated disease course. Further, the MOFA model revealed aberrant pathways of early thymopoiesis alongside enrichment of antiviral innate immunity. In line, viral prevalence, particularly of Epstein-Barr virus (EBV), trended higher in both lesional skin and the blood compared to nonlesional skin. Additionally, TCRs in both MF skin lesions and the blood were significantly more likely to recognize EBV peptides involved in latent infection. ConclusionsFirst, our findings suggest that S. aureus with its virulence factor spa fuels MF progression trough non-canonical NF-{kappa}B and IL-1B signalling. Second, our data provide insights into the potential role of viruses in MF aetiology. Last, we propose a model of microbiome-driven MF aetiopathogenesis: Thymocytes undergo initial oncologic transformation, potentially caused by viruses. After maturation and skin infiltration, an outgrowing, pathogenic S. aureus strain evokes activation and maturation into effector memory T cells, resulting in aggressive disease.