Linked Article: Fujimura et al. Br J Dermatol 2017; 176:387–394.
Immune evasion by cancer is a well-recognized mechanism that promotes tumour growth and metastases which in recent years has been shown to be amenable to therapeutic exploitation. Extramammary Paget disease (EMPD) is a rare form of skin cancer affecting apocrine glands in anogenital regions. The prognosis of the disease is good if treated early by surgical removal of the tissue, with a 5-year survival rate close to 95%. The prognosis is worse for invasive disease, partly due to the lack of definitive treatment options in this setting. Understanding the mechanisms of EMPD evolution has the potential to identify new treatment targets for this entity. In this edition of the BJD, Fujimura et al. have looked into a suspected link between Langerhans cells (LCs) and regulatory T-cell (Treg) activity in EMPD that could contribute to the immunosuppressive environment that supports tumour growth and invasion by immune evasion.
In this study, LCs in the epidermis of lesional EMPD skin were observed to express receptor activator of nuclear factor-κ B (RANK), a receptor with many downstream effects including the release of chemokine ligand (CCL)17. Using in vitro haematopoietic stem cell-derived LCs as surrogates of skin LCs, the authors show that in vitro-derived LCs produce CCL17 in response to RANK ligand in a concentration-dependent manner. CCL17 has been shown in previous work by the authors to recruit FOXP3+ Tregs in EMPD when released by macrophages in the dermis. Taken together, these results support the hypothesis that LCs also have the potential to recruit Tregs via RANK in EMPD lesions, outlining future work that is required in this field to consolidate these findings on a larger sample size.
The comparison between Treg and LC numbers in EMPD lesions showed a correlation in invasive disease. This observation requires consideration of the absolute numbers of immune cells in the analysis, which may mask underlying associations between LCs and Tregs in EMPD. In addition, as chemokine production may vary with EMPD stage, analysis of Treg number correlation with RANK and CCL17 expression within lesions will be informative. It was also notable that CCL17 production was significantly higher by macrophages than in vitro-generated LCs, suggesting a potential differential ability by these cells to recruit Tregs in situ.
The study by Fujimura et al. focused on the contribution of epidermal LCs on Treg recruitment. An interesting avenue for future exploration includes microanatomical analysis of LCs and Tregs in EMPD and the mechanisms of how LCs may influence dermal lymphocyte activity. The use of whole-mount microscopy techniques to delineate microanatomical distribution of skin leucocytes may reveal colocalization of LCs, Tregs and macrophages in EMPD. The research done by Fujimura et al. provides further insights into the mechanisms that may promote EMPD progression and invasion, forming the basis for future novel therapeutic strategies.