Mycosis fungoides-derived exosomes and their microRNA-1246 cargo: a message from the skin.

Exosomes are small extracellular vesicles containing proteins, lipids and nucleic acids that facilitate cell–cell communication, influence local and distant microenvironments, and have implications in cancer pathogenesis. MicroRNAs (miRNAs), which act as key post‐transcriptional regulators of gene expression, are an important part of the exosome content. , In recent years, evidence has accumulated that dysregulated miRNA expression interferes with tumour immunity and plays a crucial role in the pathogenesis of diverse malignancies including cutaneous T‐cell lymphoma (CTCL). , While data addressing the role of exosomes in the most common CTCL, mycosis fungoides (MF), are only just increasing, some miRNAs have already caught attention as promising candidates for much needed diagnostic and prognostic biomarkers and novel therapeutic targets. , ,

In this issue of the BJD, Moyal and colleagues elegantly implement transmission electron microscopy and nanoparticle tracking analysis to track the presence of tumour‐derived exosomes in MF and to gain insights into their miRNA profile in vitro and ex vivo. Besides demonstrating for the first time the existence of MF‐derived exosomes, the study identifies miR‐1246 as a major miRNA in the MF cell line exosomal content and confirms the importance of miR‐155 in the pathogenesis of MF (Figure 1).

Figure 1

Route of mycosis fungoides (MF)‐derived microRNA (miRNA). Formation of exosomes is one way for MF tumour cells to discharge their cell‐free miRNA to the extracellular space. Besides proteins, lipids and nucleic acids, miR‐155 and especially miR‐1246 were identified as major cargo of MF‐derived exosomes. After their release from MF cells, exosomes are incorporated by benign and malignant recipient cells of the immune system, which markedly increases the migratory capabilities of these cells. Exosomal miR‐155 significantly contributes to this migratory effect.

In general, miR‐155 overexpression is one of the best characterized features of MF disease progression and is associated with increased cancer proliferation and tumour cell survival. , , Based on this knowledge, a prospective phase II clinical trial already explores the efficacy of the anti‐miR‐155 compound Cobomarsen (MRG‐106) in MF (https://clinicaltrials.gov/ct2/show/NCT03713320). Thus, the study of Moyal and colleagues provides further evidence for the general role of miR‐155 in MF and especially its capacity to enhance cell migration of malignant MF cells. Interestingly, both miR‐155 and miR‐1246 are present in MF cell line exosomes. However, in elucidating specifically the role of tumour‐derived exosomal miRNAs (exomiRNAs), Moyal and colleagues expand their research beyond in vitro cell‐line data to ex vivo disease‐stage dependent analysis of MF exosomes and their exomiRNA content in MF patient plasma. Of interest, in the plasma of 18 patients with advanced MF, manifesting clinically with plaque and tumour skin lesions, expression of exomiR‐1246 but not exomiR‐155 was significantly higher than in plasma of healthy individuals. Regarding total circulating cell‐free miRNA (cfmiRNA), plasma levels of both cfmiR‐155 and cfmiR‐1246 were higher in patients with advanced MF than in healthy individuals, notably independent of the patient’s blood tumour burden.

Collectively, while this novel study performed by Moyal and colleagues does not yet fully explain the relevance of the MF‐derived exomiRNA, the observations especially on cfmiRNAs do suggest a direct translational application in clinics. Both cfmiR‐155 and cfmiR‐1246, together with exomiR‐1246, should be considered as MF‐associated molecular biomarkers for advanced skin disease. They may play a role as novel therapeutic targets and open a perspective towards the development of diagnostic approaches such as liquid biopsy for CTCL.

Author Contribution

Isabella Maria Pospischil: Conceptualization (equal); Project administration (equal); Visualization (equal); Writing‐original draft (equal); Writing‐review & editing (equal). Emmanuella Guenova: Conceptualization (equal); Methodology (equal); Project administration (equal); Resources (equal); Supervision (equal); Validation (equal); Visualization (equal); Writing‐original draft (equal); Writing‐review & editing (equal).