Implication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia
Demoulin, Stéphanie ; Herfs, Michael ; Somja, Joan 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The cervical transformation zone is a dynamic area of a few millimeters in which a glandular epithelium has been replaced by a squamous epithelium through a metaplastic process.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The cervical transformation zone is a dynamic area of a few millimeters in which a glandular epithelium has been replaced by a squamous epithelium through a metaplastic process.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 ▲]Detailed reference viewed: 33 (5 ULg)
Penetration mechanism of classical and deformable liposomes through pig ear skin
Gillet, Aline ; Lecomte, Frédéric ; Hubert, Pascale et al
Poster (2010, July 06)Detailed reference viewed: 38 (9 ULg)
Cytokinic response and MHC class II expression in feline dendritic cells exposed to Microsporum canis components
Mignon, Bernard ; Hubert, Pascale ; Defaweux, Valérie et al
Conference (2010)Detailed reference viewed: 54 (32 ULg)
Immune suppression in head and neck cancers: a review.
; Demoulin, Stéphanie ; Hubert, Pascale 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 ▲]Detailed reference viewed: 26 (12 ULg)
Regulation of p63 Isoforms by Snail and Slug Transcription Factors in Human Squamous Cell Carcinoma.
Herfs, Michael ; Hubert, Pascale ; Suarez-Carmona, Meggy et al
in American Journal of Pathology (2010), 176(4), 1941-1949
TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the ... [more ▼]
TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the expression of p63 is required for proper development of epithelial structures, the role of p63 in tumorigenesis remains unclear. Here, we investigated the role of Snail and Slug transcription factors, known to promote epithelial-to-mesenchymal transitions during development and cancer, in the regulation of p63 isoforms in human squamous cell carcinoma (SCC). In the present study, we observed that the expressions of DeltaN and TAp63 isoforms were, respectively, down- and up-regulated by both Snail and Slug. However, the induction of TAp63 was not directly caused by these two transcription factors but resulted from the loss of DeltaNp63, which acts as dominant-negative inhibitor of TAp63. In SCC cell lines and cancer tissues, high expression of Snail and Slug was also significantly associated with altered p63 expression. Finally, we showed that DeltaNp63 silencing reduced cell-cell adhesion and increased the migratory properties of cancer cells. These data suggest that the disruption of p63 expression induced by Snail and Slug plays a crucial role in tumor progression. Therefore, p63 and its regulating factors could constitute novel prognosis markers in patients with SCC and attractive targets for the therapeutic modulation of neoplastic cell invasiveness. [less ▲]Detailed reference viewed: 78 (18 ULg)
Implication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia
Demoulin, Stéphanie ; Somja, Joan ; Herfs, Michael et al
Poster (2010)Detailed reference viewed: 7 (0 ULg)
Local applications of GM-CSF induce the recruitment of immune cells in cervical low-grade squamous intraepithelial lesions.
Hubert, Pascale ; Doyen, Jean ; Capelle, Xavier et al
in American Journal of Reproductive Immunology (2010), 64(2), 126-136
Abstract Problem Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished ... [more ▼]
Abstract Problem Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished capacity to capture viral antigens and to induce a protective immune response. Method of study To test if a cervical application of GM-CSF could restore an immune response against HPV in women with cervical low-grade squamous intraepithelial lesions (LSIL). We performed two clinical trials with11 healthy women and 15 patients with LSIL. Results GM-CSF applications were well tolerated in all enrolled women and no difference in toxicity between the treated and placebo groups was observed during the follow up (until 30 months). Interestingly, in the GM-CSF treated group, a significant increased APC and cytotoxic T lymphocyte infiltration was observed in the cervical biopsies with no change in regulatory T cell numbers. All the HPV16+ patients exhibited an immune response against HPV16 after GM-CSF applications, as shown by NK and/or T cells producing IFN-γ whereas no cellular immune response was observed before the treatment. Moreover, the anti-VLP antibody titers also increased after the treatment. Conclusion These encouraging results obtained from a limited number of subjects justify further study on the therapeutic effect of APC in cervical (pre)neoplastic lesions. [less ▲]Detailed reference viewed: 132 (53 ULg)
The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context.
Herman, Ludivine ; Hubert, Pascale ; Herfs, Michael et al
in European Journal of Immunology (2010), 40(11), 3075-84
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately ... [more ▼]
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-kappaB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE(2)), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells. [less ▲]Detailed reference viewed: 31 (10 ULg)
Epithelial metaplasia: adult stem cell reprogramming and (pre)neoplastic transformation mediated by inflammation?
Herfs, Michael ; Hubert, Pascale ; Delvenne, Philippe
in Trends in Molecular Medicine (2009), 15(6), 245-253Detailed reference viewed: 192 (15 ULg)
High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells
Herfs, Michael ; Herman, Ludivine ; Hubert, Pascale et al
in Cancer Immunology, Immunotherapy (2009), 58(4), 603-614Detailed reference viewed: 54 (18 ULg)
Surface Mucin-1 does not play a role in dendritic cell migration
; Caberg, Jean-Hubert ; et al
in Molecular Immunology (2009), 46(4), 738-742Detailed reference viewed: 29 (3 ULg)
Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20
Caberg, Jean-Hubert ; Hubert, Pascale ; Herman, Ludivine et al
in Cancer Immunology, Immunotherapy (2009), 58(1), 39-47Detailed reference viewed: 71 (7 ULg)
Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma.
Vandermeers, Fabian ; Hubert, Pascale ; Delvenne, Philippe et al
in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2009), 15(8), 2818-28
PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to ... [more ▼]
PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and RESULTS: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patient's biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. CONCLUSIONS: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma. [less ▲]Detailed reference viewed: 61 (11 ULg)
MUCOADHESIVE PHARMACEUTICAL COMPOSITIONS COMPRISING CHEMOATTRACTANTS.
Noël, Agnès ; Herman, Ludivine ; Hubert, Pascale et al
Patent (2008)Detailed reference viewed: 24 (5 ULg)
Silencing of E7 oncogene restores functional E-cadherin expression in human papillomavirus 16-transformed keratinocytes
Caberg, Jean-Hubert ; Hubert, Pascale ; Begon, Dominique et al
in Carcinogenesis (2008), 29(7), 1441-7Detailed reference viewed: 44 (11 ULg)
Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression
Herfs, Michael ; Hubert, Pascale ; et al
in American Journal of Pathology (2008), 172(5), 1391-402
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is ... [more ▼]
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor- 1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor- 1 indirectly reduces antigenpresenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis. [less ▲]Detailed reference viewed: 71 (20 ULg)
Innate lymphocyte and dendritic cell cross-talk: a key factor in the regulation of the immune response.
Reschner, Anca ; Hubert, Pascale ; Delvenne, Philippe et al
in Clinical & Experimental Immunology (2008), 152(2), 219-26
Dendritic cells (DC) are specialized in the presentation of antigens and the initiation of specific immune responses. They have been involved recently in supporting innate immunity by interacting with ... [more ▼]
Dendritic cells (DC) are specialized in the presentation of antigens and the initiation of specific immune responses. They have been involved recently in supporting innate immunity by interacting with various innate lymphocytes, such as natural killer (NK), NK T or T cell receptor (TCR)-gammadelta cells. The functional links between innate lymphocytes and DC have been investigated widely and different studies demonstrated that reciprocal activations follow on from NK/DC interactions. The cross-talk between innate cells and DC which leads to innate lymphocyte activation and DC maturation was found to be multi-directional, involving not only cell-cell contacts but also soluble factors. The final outcome of these cellular interactions may have a dramatic impact on the quality and strength of the down-stream immune responses, mainly in the context of early responses to tumour cells and infectious agents. Interestingly, DC, NK and TCR-gammadelta cells also share similar functions, such as antigen uptake and presentation, as well as cytotoxic and tumoricidal activity. In addition, NK and NK T cells have the ability to kill DC. This review will focus upon the different aspects of the cross-talk between DC and innate lymphocytes and its key role in all the steps of the immune response. These cellular interactions may be particularly critical in situations where immune surveillance requires efficient early innate responses. [less ▲]Detailed reference viewed: 72 (24 ULg)
Crossroads between actinic keratosis and squamous cell carcinoma, and novel pharmacological issues.
Quatresooz, Pascale ; Pierard, Claudine ; Paquet, Philippe et al
in European Journal of Dermatology (2008), 18(1), 6-10
Actinic keratoses (AKs) and their derived squamous cell carcinomas are distinctive lesions forming a continuum in a multi-step carcinogenesis process. They are typically found on chronically sun exposed ... [more ▼]
Actinic keratoses (AKs) and their derived squamous cell carcinomas are distinctive lesions forming a continuum in a multi-step carcinogenesis process. They are typically found on chronically sun exposed skin. AKs merit to be recognized as such and to be distinguished from squamous cell carcinomas both conceptually and for therapeutic implications. The histological differences between these lesions are well defined and should not be blurred. A brief review is presented about the biological features responsible for AKs and the clinicopathologically distinctive aspects of these lesions. In addition, recent findings are presented about pharmacotherapy using anti-epidermal growth factor receptors, imidazoquinolines, diclofenac-hyaluronan, and methyl aminolevulinate photodynamic therapy. [less ▲]Detailed reference viewed: 64 (4 ULg)
The cross-talk between dendritic and regulatory T cells: good or evil?
Hubert, Pascale ; Jacobs, Nathalie ; Caberg, Jean-Hubert et al
in Journal of Leukocyte Biology (2007), 82(4), 781-94
Immune responses against pathogens require fine regulation in order to avoid excessive inflammation, which could be harmful to the host. Moreover, the immune system must be tolerant to non-pathogenic ... [more ▼]
Immune responses against pathogens require fine regulation in order to avoid excessive inflammation, which could be harmful to the host. Moreover, the immune system must be tolerant to non-pathogenic antigens in order to prevent allergy, autoimmunity and transplant rejection. There is accumulating evidence that interactions between dendritic cells (DC) and regulatory T (Treg) cells play a crucial role in the balance between immune response and tolerance. Communications between these cells are complex, bi-directional and mediated by soluble or cell surface molecules. The maturation status of DC, which may be influenced by different microenvironmental factors, is considered as an important checkpoint for the induction of peripheral tolerance through modifications of the activation status of T cells. Moreover, several lines of experimental evidence suggest that different subsets or the functional status of DC are also involved in the promotion of Treg cell differentiation. A better knowledge of the regulatory mechanisms of the immune response induced or inhibited by DC via their interactions with Treg cells could be relevant for the development of new immunotherapeutic approaches. [less ▲]Detailed reference viewed: 73 (13 ULg)
MIP3 alpha stimulates the migration of Langerhans cells in models of human papillomavirus (HPV)-associated (pre)neoplastic epithelium
Herman, Ludivine ; Hubert, Pascale ; Caberg, Jean-Hubert et al
in Cancer Immunology, Immunotherapy (2007), 56(7), 1087-1096Detailed reference viewed: 50 (5 ULg)