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Article ; Online: Cancer immunotherapy: it's time to better predict patients' response.

Pilard, Charlotte / Ancion, Marie / Delvenne, Philippe / Jerusalem, Guy / Hubert, Pascale / Herfs, Michael

2021 Volume 125, Issue 7, Page(s) 927–938

Abstract: In less than a decade, half a dozen immune checkpoint inhibitors have been approved and are currently revolutionising the treatment of many cancer (sub)types. With the clinical evaluation of novel delivery approaches (e.g. oncolytic viruses, cancer ... ...

Abstract	In less than a decade, half a dozen immune checkpoint inhibitors have been approved and are currently revolutionising the treatment of many cancer (sub)types. With the clinical evaluation of novel delivery approaches (e.g. oncolytic viruses, cancer vaccines, natural killer cell-mediated cytotoxicity) and combination therapies (e.g. chemo/radio-immunotherapy) as well as the emergence of novel promising targets (e.g. TIGIT, LAG-3, TIM-3), the 'immunotherapy tsunami' is not about to end anytime soon. However, this enthusiasm in the field is somewhat tempered by both the relatively low percentage (<15%) of patients who display an effective anti-cancer immune response and the inability to accurately identify them. Recently, several existing or acquired features/parameters have been shown to impact the efficacy of immune checkpoint inhibitors. In the present review, we critically discuss current knowledge regarding predictive biomarkers for checkpoint inhibitor-based immunotherapy, highlight the missing/unclear links and emphasise the importance of characterising each neoplasm and its microenvironment in order to better guide the course of treatment.
MeSH term(s)	Cancer Vaccines/therapeutic use ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Immunotherapy/methods ; Killer Cells, Natural/transplantation ; Neoplasms/immunology ; Neoplasms/therapy ; Oncolytic Virotherapy
Chemical Substances	Cancer Vaccines ; Immune Checkpoint Inhibitors
Language	English
Publishing date	2021-06-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-021-01413-x
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Article: Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy.

Hubert, Pascale / Amigorena, Sebastian

Oncoimmunology

2012 Volume 1, Issue 1, Page(s) 103–105

Abstract: Antibody-dependent cell cytotoxicity (ADCC) is critical in monoclonal antibody (mAb)-mediated cancer therapy. We recently showed that a tumor-specific mAb in combination with cyclophosphamide inhibited tumor cell growth and induced ADCC-synapses between ... ...

Abstract	Antibody-dependent cell cytotoxicity (ADCC) is critical in monoclonal antibody (mAb)-mediated cancer therapy. We recently showed that a tumor-specific mAb in combination with cyclophosphamide inhibited tumor cell growth and induced ADCC-synapses between tumor and effector cells in vivo, opening perspectives to enhance anti-tumor responses by manipulating the immune system.
Language	English
Publishing date	2012-05-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.4161/onci.1.1.17963
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Article ; Online: Defensins: "Simple" antimicrobial peptides or broad-spectrum molecules?

Suarez-Carmona, Meggy / Hubert, Pascale / Delvenne, Philippe / Herfs, Michael

Cytokine & growth factor reviews

2015 Volume 26, Issue 3, Page(s) 361–370

Abstract: Small cationic peptides highly conserved in vertebrates, both α- and β-defensins were primarily identified as anti-microbial compounds involved in innate immunity. While human α-defensins are mostly expressed by neutrophils, β-defensins are secreted by ... ...

Abstract	Small cationic peptides highly conserved in vertebrates, both α- and β-defensins were primarily identified as anti-microbial compounds involved in innate immunity. While human α-defensins are mostly expressed by neutrophils, β-defensins are secreted by epithelial cells of the skin and mucosae. Besides their anti-microbial activity, accumulating data emerged in the past decade indicating that defensins have extended functions in human physio(patho)logy. Indeed, defensins appeared as modulators of the adaptive immune system and angiogenesis, key mediators of wound healing and determinant players in male fertility. Furthermore, the impact of defensin expression in cancer and the potential use of these small peptides as biomarkers or even therapeutic tools should not be ignored. In the present review, we describe recent research works regarding the diversified functions of defensins, by mainly focusing on human models.
MeSH term(s)	Adaptive Immunity ; Animals ; Biomarkers/metabolism ; Carcinogenesis ; Defensins/immunology ; Defensins/metabolism ; Fertility ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Lymphangiogenesis ; Wound Healing
Chemical Substances	Biomarkers ; Defensins
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1330534-7
ISSN	1879-0305 ; 1359-6101
ISSN (online)	1879-0305
ISSN	1359-6101
DOI	10.1016/j.cytogfr.2014.12.005
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Article ; Online: Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair.

Theranostics

2023 Volume 13, Issue 3, Page(s) 1130–1149

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Humans ; Human Papillomavirus Viruses ; Papillomavirus Infections/radiotherapy ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Papillomavirus E7 Proteins/genetics ; DNA Repair ; DNA Damage ; Neoplasms ; Nuclear Proteins/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/metabolism ; Carrier Proteins/metabolism
Chemical Substances	Oncogene Proteins, Viral ; Papillomavirus E7 Proteins ; POLDIP2 protein, human ; Nuclear Proteins ; PNKP protein, human (EC 2.7.1.-) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; DNA Repair Enzymes (EC 6.5.1.-) ; UVSSA protein, human ; Carrier Proteins
Language	English
Publishing date	2023-01-31
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.78091
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Article ; Online: Promoting Vaginal Distribution of E7 and MCL-1 siRNA-Silencing Nanoparticles for Cervical Cancer Treatment.

Lechanteur, Anna / Furst, Tania / Evrard, Brigitte / Delvenne, Philippe / Piel, Géraldine / Hubert, Pascale

Molecular pharmaceutics

2017 Volume 14, Issue 5, Page(s) 1706–1717

Abstract: There is an urgent need to develop a less aggressive and more effective treatment against cervical lesions induced by different high-risk human papillomavirus (HR-HPV). We investigated the potential of a cocktail of small interfering RNA (siRNA) directed ...

Abstract	There is an urgent need to develop a less aggressive and more effective treatment against cervical lesions induced by different high-risk human papillomavirus (HR-HPV). We investigated the potential of a cocktail of small interfering RNA (siRNA) directed against the oncoprotein E6 (E6), the oncoprotein E7 (E7), or the antiapoptotic protein MCL-1 (MCL-1). The combination of siRNA anti-E7 and anti-MCL-1 demonstrated high efficacy on multiple HPV16 and HPV18 cell lines and no effects on healthy keratinocytes. This gene therapy has been considered for a vaginal administration since this route of application holds high potential for the treatment of diseases in the female reproductive tracts. Therefore, PEGylated lipoplexes have been designed and characterized to protect siRNA and to diffuse in the mucosal environment before they reach the cervico/vaginal epithelium. This new nanovector complexed to the combination of active siRNA induced an efficient mRNA knockdown since biological effects were obtained in vitro. This work also provided evidence that the PEGylated lipoplexes had appropriate physicochemical properties to diffuse into a mucin network according to size measurement experiments in artificial mucus. After demonstrating the distribution and the efficacy of siRNA into a 3D-cervical model lesion and through porcine vaginal mucosa, in vivo experiments in mouse have been performed under physiological conditions. This study revealed a complete and sustained coverage of the mucosal epithelium following an unique vaginal administration of fluorescent PEGylated lipoplexes. Overall, our results showed the potential of the PEGylated lipoplexes for the prolonged delivery of active siRNA to treat HPV-induced lesions.
MeSH term(s)	Animals ; Cell Line, Tumor ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Female ; Human papillomavirus 16/genetics ; Human papillomavirus 18/genetics ; Humans ; Immunohistochemistry ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Nanoparticles/chemistry ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Papillomavirus E7 Proteins/genetics ; Papillomavirus E7 Proteins/metabolism ; RNA, Small Interfering ; Swine ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/metabolism ; Uterine Cervical Neoplasms/therapy ; Vagina/metabolism
Chemical Substances	DNA-Binding Proteins ; E6 protein, Human papillomavirus type 18 ; Myeloid Cell Leukemia Sequence 1 Protein ; Oncogene Proteins, Viral ; Papillomavirus E7 Proteins ; RNA, Small Interfering ; oncogene protein E7, Human papillomavirus type 16
Language	English
Publishing date	2017-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.6b01154
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Zs.A 6250: Show issues

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Article ; Online: Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms.

Demoulin, Stéphanie / Herfs, Michael / Delvenne, Philippe / Hubert, Pascale

Journal of leukocyte biology

2013 Volume 93, Issue 3, Page(s) 343–352

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Humans ; Immune Tolerance ; Interferon Type I/immunology ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Plasma Cells/immunology ; Plasma Cells/pathology ; Tumor Escape ; Tumor Microenvironment/immunology
Chemical Substances	Cancer Vaccines ; Interferon Type I
Language	English
Publishing date	2013-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1189/jlb.0812397
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Article ; Online: Production of large numbers of plasmacytoid dendritic cells with functional activities from CD34(+) hematopoietic progenitor cells: use of interleukin-3.

Demoulin, Stéphanie / Roncarati, Patrick / Delvenne, Philippe / Hubert, Pascale

Experimental hematology

2012 Volume 40, Issue 4, Page(s) 268–278

Abstract: Plasmacytoid dendritic cells (pDC), a subset of dendritic cells characterized by a rapid and massive type-I interferon secretion through the Toll-like receptor pathway in response to viral infection, play important roles in the pathogenesis of several ... ...

Abstract	Plasmacytoid dendritic cells (pDC), a subset of dendritic cells characterized by a rapid and massive type-I interferon secretion through the Toll-like receptor pathway in response to viral infection, play important roles in the pathogenesis of several diseases, such as chronic viral infections (e.g., hepatitis C virus, human immunodeficiency virus), autoimmunity (e.g., psoriasis, systemic lupus erythematosus), and cancer. As pDC represent a rare cell type in the peripheral blood, the goal of this study was to develop a new method to efficiently generate large numbers of cells from a limited number of CD34(+) cord blood progenitors to provide a tool to resolve important questions about how pDC mediate tolerance, autoimmunity, and cancer. Human CD34(+) hematopoietic progenitor cells isolated from cord blood were cultured with a combination of Flt3-ligand (Flt3L), thrombopoietin (TPO), and one of the following cytokine: interleukin (IL)-3, interferon-β(IFN-β), or prostaglandin E2(PGE(2)). Cells obtained in the different culture conditions were analyzed for their phenotype and functional characteristics. The addition of IL-3 cooperates with Flt3L and TPO in the induction of pDC from CD34(+) hematopoietic progenitor cells. Indeed, Flt3L/TPO alone or supplemented with prostaglandin E2 or interferon-β produced smaller amounts of pDC from hematopoietic progenitor cells. In addition, pDC generated in Flt3L/TPO/IL-3 cultures exhibited morphological, immunohistochemical, and functional features of peripheral blood pDC. We showed that IL-3, in association with Flt3L and TPO, provides an advantageous tool for large-scale generation of pDC. This culture condition generated, starting from 2 × 10(5) CD34(+) cells, up to 2.6 × 10(6) pDC presenting features of blood pDC.
MeSH term(s)	Adult ; Cell Culture Techniques ; Cell Differentiation/drug effects ; Cells, Cultured/cytology ; Cells, Cultured/drug effects ; Culture Media/pharmacology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Dinoprostone/pharmacology ; Drug Synergism ; Fetal Blood/cytology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Humans ; Immunophenotyping ; Infant, Newborn ; Interferon-beta/pharmacology ; Interleukin-3/pharmacology ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/drug effects ; Membrane Proteins/pharmacology ; Oligodeoxyribonucleotides/pharmacology ; Recombinant Proteins/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Thrombopoietin/pharmacology
Chemical Substances	Culture Media ; IL3 protein, human ; Interleukin-3 ; Membrane Proteins ; Oligodeoxyribonucleotides ; Recombinant Proteins ; flt3 ligand protein ; Interferon-beta (77238-31-4) ; Thrombopoietin (9014-42-0) ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2012-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	185107-x
ISSN	1873-2399 ; 0531-5573 ; 0301-472X
ISSN (online)	1873-2399
ISSN	0531-5573 ; 0301-472X
DOI	10.1016/j.exphem.2012.01.002
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Article ; Online: PEGylation of lipoplexes: The right balance between cytotoxicity and siRNA effectiveness.

Lechanteur, Anna / Furst, Tania / Evrard, Brigitte / Delvenne, Philippe / Hubert, Pascale / Piel, Géraldine

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2016 Volume 93, Page(s) 493–503

Abstract: The delivery of small interfering RNA (siRNA) is an attractive therapeutic approach to treat several pathologies, such as viral infections or cancers. However, the stability and the efficacy of these biotherapies are still a major obstacle to their use. ... ...

Abstract	The delivery of small interfering RNA (siRNA) is an attractive therapeutic approach to treat several pathologies, such as viral infections or cancers. However, the stability and the efficacy of these biotherapies are still a major obstacle to their use. Cationic liposomes (DOTAP/Chol/DOPE 1/0.75/0.5M ratio) have been complexed to siRNA (lipoplexes) in order to be administrated by the vaginal route, in the context of HPV16 induced cervical preneoplastic lesions. To overcome the constraint of the cervico-vaginal mucus, PEGylation is required to allow the diffusion of lipoplexes through it. Thereby, PEGylated lipoplexes coated with three types of polyethylene glycol (PEG) as DSPE-PEG2000, DSPE-PEG750 or C8-PEG2000-Ceramide (Ceramide-PEG2000) at different densities have been developed and characterized. PEGylated lipoplexes were successfully prepared and showed a hydrodynamic diameter around 200nm, appropriate for vaginal application. In vitro assays on HPV16 positive cell lines revealed that a positive charge of PEGylated lipoplexes allows a higher mRNA knockdown by siRNA. However, the cationic property is also associated to cytotoxicity. The addition of a high percentage of PEG prevented this toxicity but seemed also to reduce siRNA endosomal escape, probably by steric hindrance. The decreasing of PEG density of Ceramide-PEG2000 to 20% allows the release of siRNA and in consequence, biological activities, contrarily to DSPE-PEG. These results suggest that Ceramide-PEG is more appropriate for siRNA delivery compared to DSPE-PEG. In conclusion, the right balance between cytotoxicity and siRNA effectiveness has been found with the transfection of lipoplexes coated with 20% of Ceramide-PEG2000. This new nanovector could have a high potential against multiple mucosal diseases, such as human papillomavirus-induced genital lesions.
MeSH term(s)	Cell Line, Tumor ; Cell Survival ; Ceramides/chemistry ; Human papillomavirus 16/genetics ; Humans ; Liposomes ; Oncogene Proteins, Viral/genetics ; Phosphatidylethanolamines/chemistry ; Polyethylene Glycols/chemistry ; RNA, Messenger/metabolism ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics ; Repressor Proteins/genetics ; Surface Properties
Chemical Substances	Ceramides ; E6 protein, Human papillomavirus type 16 ; Liposomes ; Oncogene Proteins, Viral ; Phosphatidylethanolamines ; RNA, Messenger ; RNA, Small Interfering ; Repressor Proteins ; 1,2-distearoylphosphatidylethanolamine (1G4B5265CQ) ; Polyethylene Glycols (30IQX730WE)
Language	English
Publishing date	2016-10-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2016.08.058
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Zs.A 3705: Show issues

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Article: TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma.

Staumont, Bernard / Jamakhani, Majeed / Costa, Chrisostome / Vandermeers, Fabian / Sriramareddy, Sathya Neelature / Redouté, Gaëlle / Mascaux, Céline / Delvenne, Philippe / Hubert, Pascale / Safari, Roghaiyeh / Willems, Luc

Cancers

2020 Volume 12, Issue 6

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2020-06-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12061484
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Article ; Online: Mucosal junctions: open doors to HPV and HIV infections?

Herfs, Michael / Hubert, Pascale / Moutschen, Michel / Delvenne, Philippe

Trends in microbiology

2011 Volume 19, Issue 3, Page(s) 114–120

Abstract: Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic ... ...

Abstract	Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic conversions are associated with chronic inflammation and deregulated expression of soluble and cell-membrane factors important for antiviral immune response. In this paper, we propose that these histological and immunological features increase the susceptibility of these metaplastic microenvironments to human papillomavirus and human immunodeficiency virus infections. Identification of the anatomical sites and cell populations within the anogenital tract, which is the site primary infected by these viruses, is crucial for the understanding of the pathogenesis of viral disease and development of antiviral strategies.
MeSH term(s)	Adult ; Alphapapillomavirus/immunology ; Alphapapillomavirus/pathogenicity ; Anal Canal/immunology ; Anal Canal/pathology ; Anal Canal/virology ; Carcinoma, Squamous Cell/immunology ; Carcinoma, Squamous Cell/pathology ; Carcinoma, Squamous Cell/virology ; Cervix Uteri/immunology ; Cervix Uteri/pathology ; Cervix Uteri/virology ; Disease Susceptibility/immunology ; Disease Susceptibility/virology ; Female ; HIV/immunology ; HIV/pathogenicity ; HIV Infections/etiology ; HIV Infections/immunology ; HIV Infections/virology ; Humans ; Intercellular Junctions/immunology ; Intercellular Junctions/pathology ; Intercellular Junctions/virology ; Intestinal Mucosa/immunology ; Intestinal Mucosa/pathology ; Intestinal Mucosa/virology ; Mucous Membrane/immunology ; Mucous Membrane/pathology ; Mucous Membrane/virology ; Papillomavirus Infections/etiology ; Papillomavirus Infections/immunology ; Papillomavirus Infections/virology ; Proctitis/complications ; Proctitis/immunology ; Proctitis/pathology ; Risk Factors ; Tumor Microenvironment/immunology ; Uterine Cervical Dysplasia/complications ; Uterine Cervical Dysplasia/immunology ; Uterine Cervical Dysplasia/pathology
Language	English
Publishing date	2011-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2010.12.006
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