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Possible mechanisms of the crosstalk between Langerhans cells and regulatory T cells in extramammary Paget disease by receptor activator of nuclear factor kappa B ( RANK ) ligand/ RANK pathways
Author(s) -
Fujimura T.,
Kambayashi Y.,
Furudate S.,
Kakizaki A.,
Hidaka T.,
Aiba S.
Publication year - 2017
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.14864
Subject(s) - rankl , stromal cell , population , cancer research , chemokine , rank ligand , pathology , biology , immunology , medicine , receptor , activator (genetics) , inflammation , environmental health
Summary Background Extramammary Paget disease ( EMPD ) is a skin adenocarcinoma of apocrine gland origin, in which Paget cells express receptor activator of nuclear factor kappa B ( RANK ) ligand ( RANKL ) and matrix metalloproteinase ( MMP )‐7, and release soluble (s) RANKL into the tumour microenvironment. We previously reported that about 60% of the RANK + cells among the stromal cells are M2 macrophages, but the identity of the remaining population of RANK + cells is still unknown. Objectives To investigate the unknown subpopulation of RANK ‐expressing cells in EMPD . Methods The main population of RANK ‐expressing cells in the epidermis was composed of epidermal Langerhans cells ( LC s). To explore the effects of RANKL on LC s, we stimulated LC s generated from human CD 34 + hematopoietic progenitor cells with graded concentrations of sRANKL . To further examine the correlation between LC s and regulatory T cells (Tregs) in EMPD , we employed immunohistochemical staining. Results sRANKL stimulation was shown to augment the production of C‐C motif chemokine ligand 17 ( CCL 17) from LC s. We additionally demonstrated CCL 17 expression by CD 1a + LC s in EMPD in an immunofluorescence study. Spearman's rank correlation test confirmed a correlation between the number of LC s and the number of Foxp3 + Tregs in the lesional skin of invasive EMPD . In addition, the numbers of Foxp3 + Tregs in the sentinel lymph nodes of metastatic EMPD were significantly higher than those of metastatic melanoma, which did not express RANKL . Conclusions The findings suggest that the RANKL / RANK pathway in EMPD might contribute to the recruitment of Tregs and to maintenance of the tumour microenvironment.