References of "Demoulin, Stéphanie"
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See detailCarcinogenic HPV infection in the cervical squamo-columnar junction
Mirkovic, Jelena; Howitt, Brooke; RONCARATI, Patrick ULg et al

in Journal of Pathology (The) (in press)

Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and ... [more ▼]

Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to 1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and 2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analyzed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16ink4, Ki67 and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from 8 of 10 with visible SCJ cells, 6 of which were HPV16/18 DNA positive. In 5 of these latter cases, the SCJ cells were positive for p16ink4 and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in micro-dissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16ink4 immunoreactivity, elevated proliferative index and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16ink4 expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ. [less ▲]

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See detailPrognosis of HPV-positive head and neck cancers : implication of smoking and immunosuppression
Duray, Anaëlle; LACREMANS, Daniel ULg; Demoulin, Stéphanie ULg et al

in Advances in Cellular and Molecular Otolaryngology (2014), 2

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See detailAltérations fonctionnelles des cellules dendritiques dans la cancérisation du col utérin
Demoulin, Stéphanie ULg

Doctoral thesis (2014)

Le cancer du col utérin (SCC) est presque universellement associé à une infection par des papillomavirus à haut risque (HR-HPV) et est une des principales causes de décès par cancer chez les femmes à ... [more ▼]

Le cancer du col utérin (SCC) est presque universellement associé à une infection par des papillomavirus à haut risque (HR-HPV) et est une des principales causes de décès par cancer chez les femmes à travers le monde. Actuellement, deux vaccins empêchant l'infection par des HR-HPV spécifiques sont disponibles, cependant, ils n'ont pas d'efficacité thérapeutique et il a été estimé qu'il n'y aura pas de baisse mesurable des cancers associés à HPV avant 2040. Même si l'infection par les HR-HPV est nécessaire à la carcinogenèse du col utérin, elle n'est pas suffisante pour le développement du cancer puisque seule une minorité des cas progresseront vers une tumeur. En effet, d’autres facteurs, liés à l’hôte ou environnementaux, qui agissent après l’infection peuvent augmenter le risque de développement cancéreux. Récemment, il a été proposé que les cellules épithéliales et/ou inflammatoires pourraient créer un environnement immunosuppresseur facilitant la transformation maligne en altérant l'immunité antitumorale. Etant donné que plusieurs études ont montré que le microenvironnement tumoral pouvait altérer la fonction des cellules dendritiques plasmacytoïdes (pDC) et conventionnelles (cDC) et les rendre tolérogènes, nous avons concentré notre attention sur ces cellules et sur leur rôle potentiel dans la cancérisation du col utérin. Dans la première partie de ce travail, nous nous sommes concentrés sur l'implication des pDC dans la cancérisation du col utérin. Nous avons d'abord montré que ces cellules sont recrutées au cours de la séquence "métaplasie-dysplasie-cancer" du col de l’utérus suite à l’augmentation de l'expression de la chémérine dans ces lésions. Etant donné que les pDC représentent un population cellulaire rare dans le sang périphérique, nous avons développé une nouvelle méthode afin de générer un grand nombre de pDC à partir d'un nombre limité de cellules progénitrices CD34+ isolées de sang de cordon ombilical. Notre but était de fournir un outil permettant de définir si la fonction de ces cellules peut être influencée par le microenvironnement tumoral. Les pDC générées in vitro présentent la morphologie, les caractéristiques phénotypiques et fonctionnelles des pDC se trouvant dans le sang périphérique. Les pDC générées in vitro ont été exposées aux molécules sécrétées dans le microenvironnement du cancer du col utérin grâce à un système de coculture. Ces pDC présentent un profil de maturation altéré, une diminution de sécrétion en IFN-α, une cytokine ayant un rôle antiviral et antitumoral. De plus, ces pDC sont capables d’induire la différenciation des lymphocytes T CD4+ naïfs en cellules T régulatrices (Treg) grâce à l’expression d’ICOSL. Les cellules Treg et les pDC forment des clusters autour des cellules cancéreuses, ce qui facilite leurs interactions. Nous avons identifié HMGB1 comme étant la molécule impliquée dans la modification du phénotype et de la fonction des pDC exposées au microenvironnement du col utérin. En parallèle, nous avons démontré que les cDC différenciées en présence de lignées de SCC du col utérin acquièrent un phénotype semi-mature et une activité fonctionnelle défectueuse, associée à une augmentation de leur sécrétion d'IL-10, une cytokine immunosuppressive. En outre, les cDC présentent également une fonction tolérogène associée à leur expression d’ILT3. L’inhibition de la voie de signalisation RANK/RANKL a permis de limiter l’effet des lignées de SCC sur les cDC. Ainsi, le cancer du col de l’utérus exploite activement la plasticité des pDC et des cDC afin de promouvoir sa progression. Des traitements ciblant HMGB1 et RANKL pourraient être utilisés afin de restaurer les activités anti-tumorales des cellules dendritiques et, par conséquent, de surmonter la tolérance immunitaire associée au microenvironnement du cancer du col utérin. [less ▲]

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See detailVulvar Skin Disorders throughout Lifetime: About Some Representative Dermatoses
DOYEN, Jean ULg; Demoulin, Stéphanie ULg; DELBECQUE, Katty ULg et al

in BioMed Research International (2014)

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See detailAltered alpha-defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour-permissive microenvironment.
Hubert, Pascale ULg; Herman, Ludivine; RONCARATI, Patrick ULg et al

in Journal of Pathology (The) (2014), 234(4), 464-77

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical ... [more ▼]

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical HPV infections into (pre)neoplastic lesions suggests that viral antigens are not adequately recognized by innate immunity or presented to the adaptive immune system. Members of the defensin family have recently been found to inhibit viral and bacterial pathogens, to stimulate the migration of immune cells and to play a role in anticancer responses. In the present study, we focused on the poorly characterized human alpha-defensin 5 (HD-5) and its possible role in these processes. We showed that HD-5 was able to prevent HPV virion entry into cervical keratinocytes and to influence adaptive immunity. Indeed, this peptide specifically induced the chemoattraction and proliferation of both activated T lymphocytes and immature dendritic cells in a CCR2/CCR6-dependent manner and stimulated the infiltration of these professional antigen-presenting cells in a (pre)neoplastic epithelium transplanted in vivo in immunodeficient mice. No chemotactic effect was observed with plasmacytoid dendritic cells, macrophages or natural killer cells. Proliferative and angiogenic effects of HD-5 were also assessed in vitro and in vivo. However there was a striking regional disparity in expression of HD-5, being prominent in ectocervical, vaginal and vulvar neoplasia, while absent, or nearly so, in the cervical SC junction. Taken together, these results suggest one possible explanation for why the SC junction is uniquely vulnerable to both high-risk HPV infection (via reduced HD-5 expression and viral entry) and progression of neoplasia (via altered cell-mediated immune responses and altered microenvironment). Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [less ▲]

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See detailHMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells
Demoulin, Stéphanie ULg; Herfs, Michael ULg; SOMJA, Joan ULg et al

in International Journal of Cancer = Journal International du Cancer (2014)

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See detailTumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms
Demoulin, Stéphanie ULg; Herfs, Michael ULg; Delvenne, Philippe ULg et al

in Journal of Leukocyte Biology (2013), 93(3), 343-352

Human pDCs represent a rare population of circulating cells characterized by a rapid and massive TLR-dependent secretion of type I IFN in response to pathogenic agents or danger signals. Through their ... [more ▼]

Human pDCs represent a rare population of circulating cells characterized by a rapid and massive TLR-dependent secretion of type I IFN in response to pathogenic agents or danger signals. Through their capacity to bring together innate and adaptive immunity and to secrete soluble factors controlling cancer development, these cells could represent important actors in antitumor immunity. However, accumulating evidence suggests that pDCs recruited to the tumor microenvironment often display a nonactivated state and are associated with the development and maintenance of immunosuppression. Here, we present an overview of neoplastic lesions associated with an infiltration of immunosuppressive/ tolerogenic pDC. Moreover, as the proper response of pDC against cancer depends on a critical balance between immune-activating and immune-suppressing mechanisms, we summarize current knowledge about the molecular pathways developed by tumors to prevent antitumoral pDC immune responses. A better understanding of the mechanisms regulating pDC function in tumors could aid in the development of new therapies. Indeed, effective cancer vaccines or therapies could combine immunoactivating strategies (i.e., TLR agonists) with elimination of immune-suppressing mechanisms, leading to pDC reprogramming and thus, allowing tumor rejection in a clinical setting. [less ▲]

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See detailBarrett's metaplasia, dysplasia and esophageal ademnocarcinoma: an inadequate antitumour immunity?
Somja, Joan ULg; Demoulin, Stéphanie ULg; Herman, Ludivine et al

Conference (2012, February 09)

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See detailImplication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia
Demoulin, Stéphanie ULg; Herfs, Michael ULg; Somja, Joan ULg et al

Poster (2010, September)

The cervical transformation zone is a dynamic area of a few millimeters in which a glandular epithelium has been replaced by a squamous epithelium through a metaplastic process. Interestingly, a ... [more ▼]

The cervical transformation zone is a dynamic area of a few millimeters in which a glandular epithelium has been replaced by a squamous epithelium through a metaplastic process. Interestingly, a substantial majority (87%) of cervical (pre)cancerous lesions develops within this peculiar microenvironment. Our previous studies reported that intrinsic immune features altered in the metaplastic epithelium could contribute to cancer development by preventing efficient antitumor/antiviral immune response. Plasmacytoid dendritic cells (pDC) are key effectors in host innate immunity and orchestrate adaptive immune responses. Recently, infiltration by these subtypes of dendritic cells has been shown in different cancers. However their implication in antitumor response is largely debated. The present study was performed to determine the implication of pDC in the cervical “metaplasia-dysplasia-cancer” sequence. We demonstrated that the density of pDC increases in the epithelium of metaplastic and (pre)cancerous cervical tissues as well as in underlying stroma as compared with normal exocervical epithelium. This could be partially explained by the increased expression of chemerin, their chemotactic peptide, observed in those areas. We developed a method to efficiently generate pDC cells exhibiting morphological and immunohistochemical features of blood pDC from a limited number of CD34+ cord blood progenitors. Using these in vitro generated pDC, we demonstrated that medium conditioned by transformed keratinocytes modified the activation status of pDC, by inducing a decreased expression of costimulatory molecules such as CD86 and HLA-DR. Moreover, malignant keratinocytes diminished the ability of pDC to produce IFNα in response to an oligonucleotide containing CpG motifs, a defined microbial stimulus for pDC. These results suggest that pDC could be educated within the metaplastic and/or (pre)cancerous microenvironment to acquire a tolerogenic phenotype that could promote carcinogenesis. In agreement with those results, we observed that both metaplastic areas and (pre)cancerous lesions of the cervix are infiltrated by T regulatory cells. [less ▲]

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See detailImmune suppression in head and neck cancers: a review.
Duray, Annaëlle; Demoulin, Stéphanie ULg; Hubert, Pascale ULg et al

in Clinical & Developmental Immunology (2010), 2010

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancer in the world. Despite significant advances in the treatment modalities involving surgery, radiotherapy, and concomitant ... [more ▼]

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancer in the world. Despite significant advances in the treatment modalities involving surgery, radiotherapy, and concomitant chemoradiotherapy, the 5-year survival rate remained below 50% for the past 30 years. The worse prognosis of these cancers must certainly be link to the fact that HNSCCs strongly influence the host immune system. We present a critical review of our understanding of the HNSCC escape to the antitumor immune response such as a downregulation of HLA class I and/or components of APM. Antitumor responses of HNSCC patients are compromised in the presence of functional defects or apoptosis of T-cells, both circulating and tumor-infiltrating. Langerhans cells are increased in the first steps of the carcinogenesis but decreased in invasive carcinomas. The accumulation of macrophages in the peritumoral areas seems to play a protumoral role by secreting VEGF and stimulating the neoangiogenesis. [less ▲]

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