Background: Mycosis fungoides (MF) represents the most prevalent entity of cutaneous T cell lymphoma (CTCL). The MF aetiopathogenesis is incompletely understood, due to significant transcriptomic heterogeneity and conflicting views on whether oncologic transformation originates in early thymocytes or mature effector memory T cells. Recently, using clinical specimens, our group showed that the skin microbiome aggravates disease course, mainly driven by an outgrowing, pathogenicS. aureusstrain carrying the virulence factor spa, which was shown by others to activate the T cell signalling pathway NF-κB. Methods: To explore the role of the skin microbiome in MF aetiopathogenesis, we here performed RNA sequencing, multi-omic 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 from our previous study group. Results: We observed that inter-patient transcriptional heterogeneity may be largely attributed to differential activation of T cell signalling pathways. Notably, the MOFA model resolved the heterogenous activation pattern of T cell signalling after denoising the transcriptome from microbial influence. The MOFA model suggested that the outgrowingS. aureusstrain evoked signalling by non-canonical NF-κB and IL-1B, which in turn may have fuelled the aggravated disease course. Further, the MOFA model indicated aberrant pathways of early thymopoiesis alongside enrichment of antiviral innate immunity. In line with this, 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. Conclusions: First, our findings suggest thatS. aureuswith its virulence factor spa fuels MF progression through non-canonical NF-κB 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, pathogenicS. aureusstrain evokes activation and maturation into effector memory T cells, resulting in aggressive disease. Further studies are warranted to verify and extend our data, which are based on computational analyses.
背景：蕈样肉芽肿（MF）是最常见的皮肤T细胞淋巴瘤（CTCL）类型。由于显著的转录组异质性以及对肿瘤转化起源于早期胸腺细胞还是成熟效应记忆T细胞存在争议观点，MF的病因发病机制尚未完全阐明。近期，我们团队利用临床样本研究发现，皮肤微生物群会加重疾病进程，这主要由携带毒力因子spa的致病性金黄色葡萄球菌过度生长驱动，而该因子已被其他研究证实可激活T细胞信号通路NF-κB。 方法：为探究皮肤微生物群在MF病因发病机制中的作用，我们对既往研究队列中的10例MF患者进行了RNA测序，采用多组学因子分析（MOFA）整合皮肤微生物组与皮肤转录组多组学数据，同时开展病毒组谱分析及T细胞受体（TCR）测序。 结果：我们发现患者间的转录异质性可能主要源于T细胞信号通路的不同激活状态。值得注意的是，MOFA模型在消除微生物对转录组的影响后，解析出T细胞信号通路的异质性激活模式。该模型提示过度生长的金黄色葡萄球菌菌株通过非经典NF-κB和IL-1B通路引发信号传导，进而可能加剧疾病进程。此外，MOFA模型显示早期胸腺生成通路异常与抗病毒天然免疫应答增强并存。与此一致的是，病毒（特别是EB病毒）在皮损皮肤和血液中的检出率均呈现高于非皮损皮肤的趋势。同时，MF皮损和血液中的TCR显著更易识别潜伏感染相关的EB病毒肽段。 结论：首先，我们的研究提示携带毒力因子spa的金黄色葡萄球菌通过非经典NF-κB和IL-1B信号通路驱动MF进展。其次，数据揭示了病毒在MF病因学中的潜在作用。最后，我们提出微生物群驱动的MF病因发病机制模型：胸腺细胞经历初始肿瘤转化（可能由病毒引发），成熟并浸润皮肤后，过度生长的致病性金黄色葡萄球菌菌株激活T细胞并促使其分化为效应记忆T细胞，最终导致侵袭性疾病。本研究基于计算分析得出，需进一步研究验证和拓展相关发现。
肿瘤(癌症)患者之家