Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas

Abstract

The present study has analysed the distribution and phenotype of dendritic cells (DCs) in primary cutaneous melanomas and sentinel lymph nodes by immunohistochemistry. In primary melanomas, an increase of DCs was found in the epidermis and the peritumoural area. Intraepidermal DCs were mostly CD1a(+)/Langerin(+) Langerhans cells. Peritumoural DCs included a large population of DC-SIGN(+)/mannose-receptor(+)/CD1a(-) DCs, a small subset of CD1a(+) DCs, and, remarkably, plasmacytoid monocytes/plasmacytoid DCs (PM/PDCs). The PM/PDCs, most likely recruited by SDF-1 secreted by melanoma cells, produced type I interferon (IFN-I), but the expression of the IFN-alpha inducible protein MxA was extremely variable and very limited in the majority of cases. All DC subsets were predominantly immature. The peritumoural area also contained a minor subset of mature CD1a(+) DCs. However, the small amount of local interleukin (IL)-12 p40 mRNA and the naïve phenotype of 20-50% of peritumoural T-lymphocytes are consistent with poor T-cell stimulation or erroneous recruitment. In sentinel lymph nodes, notable expansion of mature CD1a(+)/Langerin(+) DCs was observed. The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma-associated DCs, resulting in lack of T-cell priming. These results may explain why melanoma cells grow despite the presence of infiltrating immune cells.

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

“…Extracellular HMGB1 mediates endotoxin lethality and inflammation [32,[42][43][44][45][46]. These findings suggest that HMGB1 may be involved in regulating the function of PDC, which have been implicated in the pathogenesis of cancer [47,48] and chronic inflammatory conditions like systemic lupus erythematosus and allergy [49][50][51].…”

Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma

“…Two other studies on dendritic cell infiltrate in primary cutaneous melanoma have reported that the dendritic cell infiltrate was rare and mostly confined to the peritumoral areas. 15,21 We therefore evaluated the dendritic cell infiltrate as Absent, if 0 cells were to be found and Present otherwise. However, the DC-LAMP infiltration of the peritumoral area was more frequent and it was graded as Absent/Few versus Dense.…”

“…11 However, the DC maturation capacity is altered in tumor-bearing hosts and DC subsets in tumors are predominantly immature/nonactivated cells that mediate tolerance to the tumor by inducing Tcell anergy and regulatory T cells. 5,[12][13][14][15] The failure of immune cells in the tumor microenvironment to mount an effective immune response and their promotion of tumor progression instead may be rooted in a constitutive activation of signal transducer and activator of transcription 3 (STAT3) in both tumor cells and immune cells. STAT3 is a point of convergence for numerous oncogenic signaling pathways.…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…lupus erythematosus disease, psoriasis and rheumatoid arthritis) [1,51,52], allergic diseases (i.e. contact dermatitis and nasal mucosa polyps) [53] and in tumors [2,54] (Table 1). However, the mechanisms underlying this effect are elusive.…”

“…The relevance of PDCs in cancer immunosurveillance has been recently shown in mice [68,69], where TLR9-activated PDCs lead to the regression of subcutaneous B16 melanoma tumors, by orchestrating the sequential activation of NK cells, MDCs and CD8 + T cells. The characterization of PDCs has been performed in a variety of human neoplasms [54,[70][71][72]. However, the potential impact of PDCs for cancer immunity is based largely on in vitro studies of circulating PDCs, while PDCs detectable at the tumour site (tumor-associated PDCs, TAPDCs) are poorly characterized.…”