Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion

The progression of genital human papillomavirus (HPV) infections into preneoplastic lesions suggests that infected/malignant cells are not adequately recognized by the immune system. In this study, we demonstrated that cervical/vulvar cancer cells secrete factor(s) that affect both the maturation an...

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Bibliographic Details
Published in:Oncoimmunology 2015-06, Vol.4 (6), p.e1008334-e1008334
Main Authors: Demoulin, Stéphanie A, Somja, Joan, Duray, Anaëlle, Guénin, Samuel, Roncarati, Patrick, Delvenne, Philippe O, Herfs, Michael F, Hubert, Pascale M
Format: Article
Language:English
Subjects:
APC, antigen presenting cells
DC, dendritic cells
cervical cancers
dendritic cells
GILZ, glucocorticoid-induced leucine zipper
HPV, human papillomavirus
HSIL, high grade intraepithelial lesions
Human health sciences
IHC, immunohistochemistry
ILT3, Immunoglobulin-like transcript 3
KN, normal keratinocytes
LC, Langerhans cells
LPS, lipopolysaccharide
LSIL, low grade intraepithelial lesion
MFI, mean fluorescence intensity
Oncologie
Oncology
OPG, osteoprotegerin
Original Research
PBMC, peripheral blood mononuclear cells
pDC, plasmacytoid dendritic cells
RANKL
RANKL, Receptor activator of nuclear factor kappa-B ligand
SCC, squamous cell carcinoma
Sciences de la santé humaine
SIL, squamous intraepithelial neoplasia
tolerogenicity
Treg cells
Treg cells, regulatory T cells
VIN, vulvar intraepithelial neoplasia
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Summary:The progression of genital human papillomavirus (HPV) infections into preneoplastic lesions suggests that infected/malignant cells are not adequately recognized by the immune system. In this study, we demonstrated that cervical/vulvar cancer cells secrete factor(s) that affect both the maturation and function of dendritic cells (DC) leading to a tolerogenic profile. Indeed, DC cocultured with cancer cell lines display both a partially mature phenotype after lipopolysaccharide (LPS) maturation and an altered secretory profile (IL-10 high and IL-12p70 low ). In addition, tumor-converted DC acquire the ability to alter T-cell proliferation and to induce FoxP3 + suppressive T cells from naive CD4 + T cells. Among the immunosuppressive factors implicated in DC alterations in genital (pre)neoplastic microenvironment, we identified receptor activator of nuclear factor kappa-B ligand (RANKL), a TNF family member, as a potential candidate. For the first time, we showed that RANKL expression strongly increases during cervical progression. We also confirmed that RANKL is directly secreted by cancer cells and this expression is not related to HPV viral oncoprotein induction. Interestingly, the addition of osteoprotegerin (OPG) in coculture experiments reduces significantly the inhibition of DC maturation, the release of a tolerogenic cytokine profile (IL-12 low IL-10 high ) and the induction of regulatory T (Treg) cells. Our findings suggest that the use of inhibitory molecules directed against RANKL in cervical/vulvar (pre)neoplastic lesions might prevent alterations of DC functionality and represent an attractive strategy to overcome immune tolerance in such cancers.
ISSN:2162-4011
2162-402X
2162-402X
DOI:10.1080/2162402X.2015.1008334