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1. Protocol to generate two distinct standard-of-care murine glioblastoma models for evaluating novel combination therapies

Author

Raphael Pineau, Pierre Jean Le Reste, Tony Avril, Ulrich Jarry, Eric Chevet, and Diana Pelizzari-Raymundo

Subjects
cell culture, cancer, model organisms, molecular biology, Science (General), Q1-390
Abstract

Summary: In cancer research, murine models play a crucial role as highly valuable preclinical tools. Here, we present a protocol to generate a murine model of glioblastoma through the direct intracranial injection of tumor cells. We describe steps for cell culture, intracranial implantation, and standard-of-care treatments. We then detail procedures for monitoring tumor growth using bioluminescent imaging.For complete details on the use and execution of this protocol, please refer to Pelizzari-Raymundo et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Published
2024
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2. The Identification of New c-FLIP Inhibitors for Restoring Apoptosis in TRAIL-Resistant Cancer Cells

Author

Katherine Yaacoub, Rémy Pedeux, Pierre Lafite, Ulrich Jarry, Samia Aci-Sèche, Pascal Bonnet, Richard Daniellou, and Thierry Guillaudeux

Subjects
c-FLIP, TRAIL, apoptosis, protein–protein interaction, drug resistance, cancer treatment, Biology (General), QH301-705.5
Abstract

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following death receptors’ (DRs) activation via the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. The inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These molecules selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these nine molecules using the human lung cancer cell line H1703, overexpressing c-FLIP. Our results showed that six of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC immunoprecipitation assay. The overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis; however, a combination of TRAIL with these selected molecules significantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical molecules efficiently prevent c-FLIP recruitment into the DISC complex, thus restoring the caspase-8-dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory molecules that may serve as anticancer agents in tumors overexpressing c-FLIP.

Published
2024
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3. Afatinib or Bevacizumab in combination with Osimertinib efficiently control tumor development in orthotopic murine models of non-small lung cancer.

Author

Ulrich Jarry, Megane Bostoen, Jérome Archambeau, Raphaël Pineau, Laura Chaillot, Florence Jouan, Hélène Solhi, Hugo Ferrari, Rémy Le Guevel, Valentine Mennessier, Hervé Lena, Romain Corre, Charles Ricordel, Thierry Guillaudeux, and Rémy Pedeux

Subjects
Medicine, Science
Abstract

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

Published
2024
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4. Orthotopic model of lung cancer: isolation of bone micro-metastases after tumor escape from Osimertinib treatment

Author

Ulrich Jarry, Mégane Bostoën, Raphaël Pineau, Laura Chaillot, Valentine Mennessier, Pierre Montagne, Emilie Motte, Marjorie Gournay, Arnaud Le Goff, Thierry Guillaudeux, and Rémy Pedeux

Subjects
Orthotopic lung tumor model, Metastasis, Bioluminescence, EGFR TK inhibitor, Tumor escape, Osimertinib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Osimertinib is a third generation tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) in lung cancer. However, although this molecule is not subject to some of the resistance mechanisms observed in response to first generation TKIs, ultimately, patients relapse because of unknown resistance mechanisms. New relevant non-small cell lung cancer (NSCLC) mice models are therefore required to allow the analysis of these resistance mechanisms and to evaluate the efficacy of new therapeutic strategies. Methods Briefly, PC-9 cells, previously modified for luciferase expression, were injected into the tail vein of mice. Tumor implantation and longitudinal growth, almost exclusively localized in the lung, were evaluated by bioluminescence. Once established, the tumor was treated with osimertinib until tumor escape and development of bone metastases. Results Micro-metastases were detected by bioluminescence and collected for further analysis. Conclusion We describe an orthotopic model of NSCLC protocol that led to lung primary tumor nesting and, after osimertinib treatment, by metastases dissemination, and that allow the isolation of these small osimertinib-resistant micro-metastases. This model provides new biological tools to study tumor progression from the establishment of a lung tumor to the generation of drug-resistant micro-metastases, mimicking the natural course of the disease in human NSCLC patients.

Published
2021
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5. Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo

Author

Noémie Joalland, Laura Lafrance, Thibauld Oullier, Séverine Marionneau-Lambot, Delphine Loussouarn, Ulrich Jarry, and Emmanuel Scotet

Subjects
human vγ9vδ2 t lymphocytes, zoledronate, chemotherapy, immunotherapy, epithelial ovarian cancer, orthotopic xenograft mouse model, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate

Published
2019
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7. Supplementary Table T1 from NKG2D Controls Natural Reactivity of Vγ9Vδ2 T Lymphocytes against Mesenchymal Glioblastoma Cells

Author

Claire Pecqueur, Emmanuel Scotet, Henri Vié, François M. Vallette, Xavier Saulquin, Laetitia Gautreau-Rolland, Catherine Gratas, Lisa Oliver, Christelle Retière, Catherine Willem, Laura Lafrance, Ulrich Jarry, Jeanne Perroteau, Noémie Joalland, and Cynthia Chauvin

Abstract

Genomic information of primary GBM cultures

Published
2023
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9. Data from NKG2D Controls Natural Reactivity of Vγ9Vδ2 T Lymphocytes against Mesenchymal Glioblastoma Cells

Author

Claire Pecqueur, Emmanuel Scotet, Henri Vié, François M. Vallette, Xavier Saulquin, Laetitia Gautreau-Rolland, Catherine Gratas, Lisa Oliver, Christelle Retière, Catherine Willem, Laura Lafrance, Ulrich Jarry, Jeanne Perroteau, Noémie Joalland, and Cynthia Chauvin

Abstract

Purpose:Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of nonalloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, in vitro and in vivo, in the absence of any prior sensitization.Experimental Design:Through functional and transcriptomic analyses, we extensively characterized the immunoreactivity of human Vγ9Vδ2 T lymphocytes against various primary GBM cultures directly derived from patient tumors.Results:We evidenced that GBM cells displaying a mesenchymal signature are spontaneously eliminated by allogeneic human Vγ9Vδ2 T lymphocytes, a reactivity process being mediated by γδ T-cell receptor (TCR) and tightly regulated by cellular stress–associated NKG2D pathway. This led to the identification of highly reactive Vγ9Vδ2 T lymphocyte populations, independently of a specific TCR repertoire signature. Moreover, we finally provide evidence of immunotherapeutic efficacy in vivo, in the absence of any prior tumor cell sensitization.Conclusions:By identifying pathways implicated in the selective natural recognition of mesenchymal GBM cell subtypes, accounting for 30% of primary diagnosed and 60% of recurrent GBM, our results pave the way for novel targeted cellular immunotherapies.

Published
2023
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10. Supplementary Tables from Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Author

Claire Pecqueur, François M. Vallette, Jean-Claude Martinou, Vincent Compan, Delphine Loussouarn, Fabien Gautier, Raluca Teusan, Marie-Clotilde Alves-Guerra, Marion Rabe, Emmanuel Scotet, Ulrich Jarry, Fanny Geraldo, Catherine Gratas, Lisa Oliver, Cynthia Chauvin, and Kristell Oizel

Abstract

Sup Table 1 : metabolic phenotyping; Sup Table 2 : List of primers

Published
2023
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11. Figure S2 from NKG2D Controls Natural Reactivity of Vγ9Vδ2 T Lymphocytes against Mesenchymal Glioblastoma Cells

Author

Claire Pecqueur, Emmanuel Scotet, Henri Vié, François M. Vallette, Xavier Saulquin, Laetitia Gautreau-Rolland, Catherine Gratas, Lisa Oliver, Christelle Retière, Catherine Willem, Laura Lafrance, Ulrich Jarry, Jeanne Perroteau, Noémie Joalland, and Cynthia Chauvin

Abstract

Expression of Vγ9VÎ'2 T lymphocyte activation-related molecules in primary GBM cultures.

Published
2023
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12. A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease

Author

Antoine Cazelles, Maxime K. Collard, Yoann Lalatonne, Sabrina Doblas, Magaly Zappa, Camélia Labiad, Dominique Cazals-Hatem, Léon Maggiori, Xavier Treton, Yves Panis, Ulrich Jarry, Thomas Desvallées, Pierre-Antoine Eliat, Raphaël Pineau, Laurence Motte, Didier Letourneur, Teresa Simon-Yarza, Eric Ogier-Denis, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Avicenne [AP-HP], Biotrial, Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme Rennaise d'Imagerie et Spectroscopie Structurale et Métabolique (PRISM), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), French National Institute of Health INSERM, Fondation pour la Recherche Medicale [M2R201906008873], INSERM-Transfert CoPoC, Idex Pre-maturation 'Universite Paris 2019', Conseil Regional de Bretagne (SAD 2021), Rennes Metropole (AIS 2021), and Jonchère, Laurent

Subjects
Male, [SDV]Life Sciences [q-bio], Crohn’s disease, perianal fistula, preclinical model, iron oxide nanoparticles, fistula treatment, Catalysis, Inorganic Chemistry, Rats, Sprague-Dawley, Crohn Disease, Animals, Rectal Fistula, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Organic Chemistry, General Medicine, Computer Science Applications, Rats, [SDV] Life Sciences [q-bio], Crohn's disease, Treatment Outcome, Quality of Life, Magnetic Iron Oxide Nanoparticles, Neoplasm Recurrence, Local
Abstract

International audience; Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.

Published
2022
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13. In vitro long term differentiation and functionality of three-dimensional bioprinted primary human hepatocytes: application for in vivo engraftment

Author

Marie Cuvellier, Sophie Rose, Frédéric Ezan, Ulrich Jarry, Hugo de Oliveira, Arnaud Bruyère, Christophe Drieu La Rochelle, Vincent Legagneux, Sophie Langouët, Georges Baffet, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biotrial, Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cuvellier, Marie

Subjects
3D culture, 3D bioprinting, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Biomedical Engineering, Bioengineering, General Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biochemistry, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Biomaterials, primary human hepatocytes, methacrylated gelatin, tissue engineering, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Biotechnology
Abstract

In recent decades, 3D in vitro cultures of primary human hepatocytes (PHHs) have been increasingly developed to establish models capable of faithfully mimicking main liver functions. The use of 3D bioprinting, capable of recreating structures composed of cells embedded in matrix with controlled microarchitectures, is an emergent key feature for tissue engineering. In this work, we used an extrusion-based system to print PHH in a methacrylated gelatin (GelMa) matrix. PHH bioprinted in GelMa rapidly organized into polarized hollow spheroids and were viable for at least 28 d of culture. These PHH were highly differentiated with maintenance of liver differentiation genes over time, as demonstrated by transcriptomic analysis and functional approaches. The cells were polarized with localization of apico/canalicular regions, and displayed activities of phase I and II biotransformation enzymes that could be regulated by inducers. Furthermore, the implantation of the bioprinted structures in mice demonstrated their capability to vascularize, and their ability to maintain human hepatic specific functions for at least 28 d was illustrated by albumin secretion and debrisoquine metabolism. This model could hold great promise for human liver tissue generation and its use in future biotechnological developments.

Published
2022
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14. Radiosensitizing Fe-Au Nanocapsules (Hybridosomes®) increase survival of GL261 brain tumor-bearing mice treated by radiotherapy

Author

Thierry Guillaudeux, Fabienne Gauffre, Rémy Pedeux, Mégane Bostoën, Ulrich Jarry, Myrtil L. Kahn, Clément Goubault, Pierre-Antoine Eliat, Soizic Chevance, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biotrial, Plate-forme Rennaise d'Imagerie et Spectroscopie Structurale et Métabolique (PRISM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogenesis, Stress, Signaling (OSS), This work was supported by Biosit (Univ Rennes, CNRS, INSERM, BIOSIT-UMS 3480, US_S 018, Rennes F-35000 , France), the University of Rennes 1, the CNRS (Centre National de la Recherche Scientifique), the LCC (Laboratoire de Chimie de Coordination, UPR 8241), and the Région Bretagne (ARED- 107/ NAPOLI)., Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biosit, University of Rennes 1, CNRS (Centre National de la Recherche Scientifique), LCC (Laboratoire de Chimie de Coordination, UPR 8241), Région Bretagne (ARED-107/ NAPOLI), Chevance, Soizic, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Iron Oxide and Gold Hybridosome® IR Irradiation MRI, Glioblastoma H®, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, medicine.medical_treatment, Metal Nanoparticles, Pharmaceutical Science, Medicine (miscellaneous), [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Hybridosomes®, Mice, chemistry.chemical_compound, 0302 clinical medicine, Magnetic Resonance Imaging NP, General Materials Science, Reactive Oxygen Species SPION, Iron oxide Hybridosome®, Blood Brain Barrier, 0303 health sciences, Brain Neoplasms, Iron oxide Hybridosome® H(Fe Au), SPION, ROS, H®, Magnetic Resonance Imaging, 3. Good health, MRI and bioluminescence, 030220 oncology & carcinogenesis, Blood Brain Barrier GBM, NTA, Molecular Medicine, H(Fe, Combined therapies, Iron oxide nanoparticles, Nanoparticle Tracking Analysis ROS, Iron Oxide and Gold Hybridosome®, MRI, Nanoparticle Tracking Analysis, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Biomedical Engineering, Brain tumor, Au), Bioengineering, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, GBM, Nanocapsules, NP, Hybridosome® H(Fe), 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, In vivo, Cell Line, Tumor, medicine, Animals, Chemotherapy, [CHIM]Chemical Sciences, H(Fe), mouse models, nanoparticle(s) NTA, 030304 developmental biology, Chemotherapy Mouse Models, iron oxide superparamagnetic nanoparticles, Radiotherapy, business.industry, Hybridosome®, Cancer, medicine.disease, nanoparticle(s), iron oxide superparamagnetic nanoparticles TEM, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Transmission Electron Microscopy Glioblastoma, Radiation therapy, chemistry, Cancer research, IR, TEM, Nanoparticles, Irradiation, Gold, business, Reactive Oxygen Species, Glioblastoma, BBB
Abstract

International audience; Glioblastoma remains a cancer for which the effectiveness of treatments has shown little improvement over the last decades. For this pathology, multiple therapies combining resection, chemotherapy and radiotherapy remain the norm. In this context, the use of high-Z nanoparticles such as gold or hafnium to potentiate radiotherapy is attracting more and more attention. Here, we evaluate the potentiating effect of hollow shells made of gold and iron oxide nanoparticles (hybridosomes®) on the radiotherapy of glioblastoma, using murine GL261-Luc+ brain tumor model. While iron oxide seems to have no beneficial effect for radiotherapy, we observe a real effect of gold nanoparticles —despite their low amount— with a median survival increase of almost 20% compared to radiotherapy only and even 33% compared to the control group. Cellular and in vivo studies show that a molecule of interest nano-precipitated in the core of the hybridosomes® is released and internalized by the surrounding brain cells. Finally, in vivo studies show that hybridosomes® injected intra-tumorally are still present in the vicinity of the brain tumor more than 5 days after injection (duration of the Stupp protocol’s radiation treatment). Interestingly, one mouse treated with radiotherapy in the presence of gold-containing hybridosomes® survived 78 days. Monitoring of the tumoral growth of this long-term survivor using both MRI and bioluminescence revealed a decrease of the tumor size after treatment. These very encouraging results are a proof-of-concept that hybridosomes®, are really effective tools for combined therapies development (chemo-radiotherapy).

Published
2021
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15. The Ouzo effect: A tool to elaborate high-payload nanocapsules

Author

Stéphanie Dutertre, Agnès Burel, Clément Goubault, Mégane Bostoën, Marie-Bérengère Troadec, Ulrich Jarry, Fabienne Gauffre, Olivier Mongin, Flavien Sciortino, Soizic Chevance, Hélène Jakobczyk, Myrtil L. Kahn, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique, Région Bretagne, UMS BIOSIT, Jonchère, Laurent, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Polymers, [SDV]Life Sciences [q-bio], Pharmaceutical Science, 02 engineering and technology, Hybridosomes®, Nanocapsules, 03 medical and health sciences, chemistry.chemical_compound, Ouzo effect, Hydrophobic cargo, [CHIM] Chemical Sciences, [CHIM]Chemical Sciences, Butylated hydroxytoluene, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Liposome, Polymer, 021001 nanoscience & nanotechnology, Fluorescence, [SDV] Life Sciences [q-bio], Membrane, chemistry, Chemical engineering, Solvents, Nanoparticles, Encapsulation, Nanoprecipitation, 0210 nano-technology, Ternary operation, Hydrophobic and Hydrophilic Interactions
Abstract

International audience; We investigate the encapsulation in hybridosomes®, a type of capsules unique regarding their structure and method of elaboration. Hybridosomes® are made of a single shell of inorganic nanoparticles (~5 nm) crosslinked with a polymer and are easily obtained via spontaneous emulsification in a ternary mixture THF/water/butylated hydroxytoluene (BHT). Our main finding is that an exceptionally high concentration of a hydrophobic model dye can be loaded in the hybridosomes®, up to 0.35 mol.L or equivalently 170 g.L or 450,000 molecules/capsule. The detailed investigation of the encapsulation mechanism shows that the dye concentrates in the droplets during the emulsification step simultaneously with capsule formation. Then it precipitates inside the capsules during the course of solvent evaporation. In vitro fluorescence measurements show that the nano-precipitated cargo can be transferred from the core of the hybridosomes® to the membrane of liposomes. In vivo studies suggest that the dye diffuses through the body during several days. The released dye tends to accumulate in body-fat, while the inorganic nanoparticles remain trapped into the liver and the spleen macrophages.

Published
2020
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16. The doubling potential of T lymphocytes allows clinical-grade production of a bank of genetically modified monoclonal T-cell populations

Author

Henri Vié, Régine Vivien, Philippe Lemarre, Valérie Chabaud, Soraya Saiagh, Béline Jesson, Patrice Chevallier, Thierry Guillaume, Ulrich Jarry, Catherine Godon, Béatrice Clémenceau, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Helixio Biopôle Clermont-Limagne [Saint-Beauzire], Etablissement Français du Sang [Pays de la Loire] (EFS - Site de Nantes), Hôpital Hôtel-Dieu [Nantes] (Centre Hospitalier Universitaire de Nantes), This study was funded by the programme hospitalier de recherche clinique (PHRC) (PHRC-K15-026/020-GUILLAUME) and institutional funding from INSERM., Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications ( CRCINA - Département INCIT - Equipe 1 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Unité de Thérapie Cellulaire et Génique [CHU Nantes] ( UTCG ), Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Etablissement Français du Sang [Pays de la Loire] ( EFS - Site de Nantes ), Hôpital Hôtel-Dieu [Nantes] ( Centre Hospitalier Universitaire de Nantes ), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, Cancer Research, Adoptive cell transfer, T-Lymphocytes, Transgene, medicine.medical_treatment, T cell, Cytological Techniques, Immunology, Blood Donors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, Biology, T-cell bank, Thymidine Kinase, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Interferon-gamma, Mice, graft-versus-tumor, 03 medical and health sciences, Transduction (genetics), [SDV.CAN] Life Sciences [q-bio]/Cancer, population doubling, Transduction, Genetic, medicine, Animals, Humans, Immunology and Allergy, HLA-DP beta-Chains, Genetics (clinical), clone, Transplantation, HLA-DP, Genes, Transgenic, Suicide, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Biology, Suicide gene, Xenograft Model Antitumor Assays, Molecular biology, Clone Cells, Genetically modified organism, 030104 developmental biology, medicine.anatomical_structure, Oncology, Monoclonal, Interleukin-2, allogeneic effect, Lymphocyte Culture Test, Mixed
Abstract

International audience; Background aims. To produce an anti-leukemic effect after hematopoietic stem cell transplantation we have long considered the theoretical possibility of using banks of HLA-DP specific T-cell clones transduced with a suicide gene. For that application as for any others, a clonal strategy is constrained by the population doubling (PD) potential of T cells, which has been rarely explored or exploited. Methods. We used clinical-grade conditions and two donors who were homozygous and identical for all HLA-alleles except HLA-DP. After mixed lymphocyte culture and transduction, we obtained 14 HLA-DP–specific T-cell clones transduced with the HSV-TK suicide gene. Clones were then selected on the basis of their specificity and functional characteristics and evaluated for their doubling potential. Results. After these steps of selection the clone NAT-DP4[(TK)], specific for HLA-DPB1*04:01/04:02, which produced high levels of interferon-γ (IFNγ), tumor necrosis factor (TNF), interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was fully sequenced. It has two copies of the HSV-TK suicide transgene whose localizations were determined. Four billion NAT-DP4[(TK)] cells were frozen after 50 PDs. Thawed NAT-DP4[(TK)] cells retain the potential to undergo 50 additional PDs, a potential very far beyond that required to produce a biological effect. This PD potential was confirmed on 6/16 additional different T-cell clones. This type of well-defined clone can also support a second genetic modification with CAR constructs. Conclusion. The possibility of choosing rare donors and exploiting the natural proliferative potential of T lymphocytes may dramatically reduce the clinical and immunologic complexity of adoptive transfer protocols that rely on the use of third-party T-cell populations.

Published
2018
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17. NKG2D controls natural reactivity of Vγ9Vδ2 T lymphocytes against mesenchymal glioblastoma cells: Vγ9Vδ2 T lymphocytes react against mesenchymal glioblastoma

Author

Noémie Joalland, Laetitia Gautreau-Rolland, Christelle Retière, Cynthia Chauvin, Emmanuel Scotet, Ulrich Jarry, Jeanne Perroteau, François M. Vallette, Xavier Saulquin, Catherine Gratas, Lisa Oliver, Laura Lafrance, Catherine Willem, Claire Pecqueur, Henri Vié, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Etablissement Français du Sang [Nantes], Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, and This work was supported by INSERM, CNRS, Université de Nantes, Association pour la Recherche contre le Cancer, Institut National du Cancer (INCa#PLBio2013-201, #PLBio2014-155), Ligue Nationale contre le Cancer. This work was realized in the context of the LabEX IGO and the IHU-Cesti programs, supported by the National Research Agency Investissements d’Avenir via the programs ANR-11-LABX-0016-01 and ANR-10-IBHU-005, respectively. The IHU-Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region.

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, T cell, Mesenchymal Glioblastoma, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, Mice, Inbred NOD, T-Lymphocyte Subsets, Tumor Cells, Cultured, medicine, Animals, Humans, Cell Proliferation, Mesenchymal stem cell, T-cell receptor, glioblastoma, Mesenchymal Stem Cells, Receptors, Antigen, T-Cell, gamma-delta, Immunotherapy, T lymphocyte, Prognosis, NKG2D, molecular subtype, Xenograft Model Antitumor Assays, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, Cancer research, immunotherapy, Vγ9Vδ2 T lymphocytes, Human
Abstract

Purpose: Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of nonalloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, in vitro and in vivo, in the absence of any prior sensitization. Experimental Design: Through functional and transcriptomic analyses, we extensively characterized the immunoreactivity of human Vγ9Vδ2 T lymphocytes against various primary GBM cultures directly derived from patient tumors. Results: We evidenced that GBM cells displaying a mesenchymal signature are spontaneously eliminated by allogeneic human Vγ9Vδ2 T lymphocytes, a reactivity process being mediated by γδ T-cell receptor (TCR) and tightly regulated by cellular stress–associated NKG2D pathway. This led to the identification of highly reactive Vγ9Vδ2 T lymphocyte populations, independently of a specific TCR repertoire signature. Moreover, we finally provide evidence of immunotherapeutic efficacy in vivo, in the absence of any prior tumor cell sensitization. Conclusions: By identifying pathways implicated in the selective natural recognition of mesenchymal GBM cell subtypes, accounting for 30% of primary diagnosed and 60% of recurrent GBM, our results pave the way for novel targeted cellular immunotherapies.

Published
2019
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18. Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts

Author

Cynthia Chauvin, Ulrich Jarry, Claire Pecqueur, Emmanuel Scotet, Béatrice Clémenceau, Noémie Joalland, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), and Bernardo, Elizabeth

Subjects
Adult, lymphocytes, Adoptive cell transfer, adoptive transfer, General Chemical Engineering, medicine.medical_treatment, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Issue 139, medicine, Animals, Humans, Cytotoxic T cell, Primary Brain Tumors, Immunology and Infection, Cancer, 030304 developmental biology, 0303 health sciences, General Immunology and Microbiology, Brain Neoplasms, business.industry, General Neuroscience, glioblastoma, Immunotherapy, stereotaxy, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, medicine.anatomical_structure, Cancer research, Heterografts, immunotherapy, business, 030217 neurology & neurosurgery, Glioblastoma
Abstract

International audience; Glioblastoma multiforme (GBM), the most frequent and aggressive primary brain cancer in adults, is generally associated with a poor prognosis, and scarce efficient therapies have been proposed over the last decade. Among the promising candidates for designing novel therapeutic strategies, cellular immunotherapies have been targeted to eliminate highly invasive and chemo-radioresistant tumor cells, likely involved in a rapid and fatal relapse of this cancer. Thus, administration(s) of allogeneic GBM-reactive immune cell effectors, such as human Vϒ9Vδ2 T lymphocytes, in the vicinity of the tumor would represents a unique opportunity to deliver efficient and highly concentrated therapeutic agents directly into the site of brain malignancies. Here, we present a protocol for the preparation and the stereotaxic administration of allogeneic human lymphocytes in immunodeficient mice carrying orthotopic human primary brain tumors. This study provides a preclinical proof-of-concept for both the feasibility and the antitumor efficacy of these cellular immunotherapies that rely on stereotactic injections of allogeneic human lymphocytes within intrabrain tumor beds.

Published
2018
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19. IL-21 Increases the Reactivity of Allogeneic Human Vγ9Vδ2 T Cells Against Primary Glioblastoma Tumors

Author

Cynthia Chauvin, Ulrich Jarry, Lisa Oliver, Claire Pecqueur, Noémie Joalland, François M. Vallette, Emmanuel Scotet, Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Supported by INSERM, CNRS, Université de Nantes, Association pour la Recherche contre le Cancer (R10139NN), Institut National du Cancer (INCa, PLBio2013-201, PLBio2014-155), Agence Nationale de la Recherche (ANR, GDSTRESS), Ligue Nationale contre le Cancer (AO InterRegional 2012)., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Adult, Cytotoxicity, Immunologic, 0301 basic medicine, Isoantigens, Cancer Research, Adoptive cell transfer, T-Lymphocytes, medicine.medical_treatment, T cell, Primary Cell Culture, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Lymphocyte Activation, Cancer Vaccines, Immunotherapy, Adoptive, γδ T cells, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Mice, Inbred NOD, Cell Line, Tumor, medicine, Animals, Humans, Immunology and Allergy, cancer, Cytotoxicity, Pharmacology, biology, Brain Neoplasms, business.industry, Interleukins, Receptors, Antigen, T-Cell, gamma-delta, Immunotherapy, cytokines, 3. Good health, Granzyme B, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Perforin, 030220 oncology & carcinogenesis, biology.protein, Cancer research, immunotherapy, Glioblastoma, business
Abstract

International audience; Glioblastoma multiforme (GBM) remains the most frequent and deadliest primary brain tumor in adults despite aggressive treatments, because of the persistence of infiltrative and resistant tumor cells. Nonalloreactive human Vγ9Vδ2 T lymphocytes, the major peripheral γδ T-cell subset in adults, represent attractive effectors for designing immunotherapeutic strategies to track and eliminate brain tumor cells, with limited side effects. We analyzed the effects of ex vivo sensitizations of Vγ9Vδ2 T cells by IL-21, a modulating cytokine, on their cytolytic reactivity. We first showed that primary human GBM-1 cells were naturally eliminated by allogeneic Vγ9Vδ2 T lymphocytes, through a perforin/granzyme-mediated cytotoxicity. IL-21 increased both intracellular granzyme B levels and cytotoxicity of allogeneic human Vγ9Vδ2 T lympho-cytes in vitro. Importantly, IL-21-enhanced cytotoxicity was rapid, which supports the development of sensitization(s) of γδ T lym-phocytes before adoptive transfer, a process that avoids any dele-terious effect associated with direct administrations of IL-21. Finally, we showed, for the first time, that IL-21-sensitized alloge-neic Vγ9Vδ2 T cells significantly eliminated GBM tumor cells that developed in the brain after orthotopic administrations in vivo. Altogether our observations pave the way for novel efficient ster-eotaxic immunotherapies in GBM patients by using IL-21-sensitized allogeneic human Vγ9Vδ2 T cells.

Published
2018

20. Efficiently stimulated adult microglia cross-prime naive CD8+T cells injected in the brain

Author

Ulrich Jarry, Laurent Pineau, Sabrina Donnou, Yves Delneste, Dominique Couez, and Pascale Jeannin

Subjects
0303 health sciences, Microglia, medicine.medical_treatment, Immunology, Antigen presentation, Inflammation, Immunotherapy, Biology, 3. Good health, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, In vivo, medicine, Immunology and Allergy, Cytotoxic T cell, medicine.symptom, 030217 neurology & neurosurgery, CD8, Neuroinflammation, 030304 developmental biology
Abstract

Microglia are the major myeloid-immune cells of the brain parenchyma. In a steady state, microglia monitor their environment for pathogens or damaged cells. In response to neural injury or inflammation, microglia become competent APCs able to prime CD4+ and CD8+ T lymphocytes. We previously demonstrated that neonatal and adult microglia cross-present exogenous soluble Ags in vitro. However, whether microglia are able to cross-present Ag to naive CD8+ T cells in vivo, within the brain microenvironment, remains undetermined. Here, we have designed an original protocol in order to exclude the involvement in cross-presentation activity of peripheral migrating APCs and of CNS-associated APCs. In C57Bl/6 mice, in which the body but not the head has been properly irradiated, we analyzed the ability of resident microglia to stimulate intracerebrally injected CD8+ T cells in vivo. This study demonstrates for the first time that adult microglia cross-present Ag to naive CD8+ T cells in vivo and that full microglia activation is required to overcome the inhibitory constrains of the brain and to render microglia able to cross-prime naive CD8+ T cells injected in the brain. These observations offer new insights in brain-tumor immunotherapy based on the induction of cytotoxic antitumoral T cells.

Published
2013
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21. FVB/N Mice Spontaneously Heal Ulcerative Lesions Induced by Mycobacterium ulcerans and Switch M. ulcerans into a Low Mycolactone Producer

Author

Céline Beauvillain, Laurent Marsollier, Caroline Savary, Yves Delneste, Estelle Marion, Camille Cano, Frédéric Altare, Pascale Jeannin, Ulrich Jarry, Laurence Preisser, Marie Robbe-Saule, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de pathologie cellulaire et Tissulaire, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Immunologie et d'Allergologie, Université d'Angers - Faculté de médecine (UA UFR Médecine), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), and Bernardo, Elizabeth

Subjects
0301 basic medicine, Buruli ulcer, Remission, Spontaneous, 030106 microbiology, Immunology, Mice, Inbred Strains, Spontaneous remission, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Biology, Mice, 03 medical and health sciences, chemistry.chemical_compound, Species Specificity, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, medicine, Animals, Humans, Immunology and Allergy, Mycolactone, Buruli Ulcer, Mice, Inbred BALB C, Innate immune system, Mycobacterium ulcerans, Gene Expression Regulation, Bacterial, medicine.disease, biology.organism_classification, Immunity, Innate, Pathophysiology, Mice, Inbred C57BL, Disease Models, Animal, chemistry, Host-Pathogen Interactions, Macrolides
Abstract

Buruli ulcer, a debilitating disease, is caused by Mycobacterium ulcerans. The incidence of this neglected tropical disease is steadily increasing. As a rule, without treatment, skin ulcers occur and a lengthy healing process may be observed associated with severe functional disabilities. Mouse models are already available to study establishment of lesions or evaluation of therapy but a lack of a suitable animal model, mimicking all clinical stages, in particular the healing process, remains an obstacle to understand the pathophysiology of M. ulcerans infection. M. ulcerans was s.c. inoculated in three consanguine mouse strains, that is, BALB/c and C57BL/6, classically used to study mycobacterial infection, and FVB/N. Strikingly, FVB/N mice, although as sensitive as all other mouse strains with respect to M. ulcerans infection, presented a spontaneous healing after the ulcerative phase despite stable bacterial load, and mycolactone toxin was not detected in the healed tissues. The spontaneous healing process was accompanied by an activation of the innate immune system. The adaptive response initiated by FVB/N mice was not involved in the healing process and did not confer protection against M. ulcerans. Our work highlights the importance of innate immune responses to control M. ulcerans infection. This in vivo model of M. ulcerans infection now paves the way for new avenues of research toward the elucidation of critical stages of this disease, such as the characterization of the regulation of mycolactone production, a better understanding of the pathophysiology of M. ulcerans infection, and the development of new therapeutic strategies.

Published
2016

22. Neonatal and adult microglia cross-present exogenous antigens

Author

Yves Delneste, Pascale Jeannin, Ulrich Jarry, Dominique Couez, Hugues Gascan, Céline Beauvillain, Pierre Guermonprez, Mari Scotet, and Sabrina Donnou

Subjects
Aging, Proteasome Endopeptidase Complex, Ovalbumin, CD8 Antigens, T-Lymphocytes, Antigen presentation, Antigen-Presenting Cells, Genes, MHC Class I, Mice, Transgenic, Major histocompatibility complex, Cell Line, Mice, Cellular and Molecular Neuroscience, Antigen, MHC class I, medicine, Animals, Antigens, Antigen-presenting cell, Cells, Cultured, Neuroinflammation, Inflammation, biology, Microglia, Flow Cytometry, Cell biology, Mice, Inbred C57BL, Phenotype, medicine.anatomical_structure, Animals, Newborn, Neurology, Immunology, biology.protein, CD8
Abstract

Some observations have suggested that cells from the central nervous system (CNS) could present exogenous antigens on major histocompatibility complex (MHC) class I molecules to CD8(+) T cells (a process called cross-presentation). Microglia are the major myeloid immunocompetent cells of the CNS. When activated, following the injury of the nervous parenchyma, they become fully competent antigen-presenting cells (APC) that prime CD4(+) T lymphocytes. We therefore tested the cross-presentation capacity of murine microglia. We report that a microglial cell line (C8-B4), neonatal microglia, and interestingly adult microglia cross-present soluble exogenous antigen (ovalbumin) to a OVA-specific CD8(+) T-cell hybridoma and cross-prime OVA-specific naive OT-1 CD8(+) T cells. In both these cases, C8-B4 and neonatal microglia cross-present OVA as well as peritoneal macrophages. Although cross-presentation by adult microglia is less efficient, it is increased by GM-CSF and CpG oligodeoxynucleotide (ODN) stimulation. Using microglial cells either exposed to an inhibitor of proteasome, lactacystin, or purified from TAP(-/-) mice, we demonstrate that the microglia cross-present antigen in proteasome- and TAP-dependant pathways, respectively. Last, microglia purified from adult mice injected intracerebrally with OVA efficiently stimulate OVA-specific CD8(+) T cells, thereby showing that microglia take up and process exogenous antigen into MHC class I in vivo. This first demonstration of the cross-presentation property of microglia offers novel therapeutic approaches to modulate CD8 T-cell responses in the brain.

Published
2008
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23. Treg depletion followed by intracerebral CpG-ODN injection induce brain tumor rejection

Author

Yves Delneste, Marie Vincent, Laurent Pineau, Pascale Jeannin, Sabrina Donnou, Isabelle Frémaux, Ulrich Jarry, Dominique Couez, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Time Factors, Lymphoma, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cell, NK cells, T-Lymphocytes, Regulatory, Mice, Immunology and Allergy, Antigens, Ly, Etoposide, Brain Neoplasms, hemic and immune systems, Flow Cytometry, 3. Good health, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, Treg, medicine.anatomical_structure, Neurology, Oligodeoxyribonucleotides, Cytokines, NK Cell Lectin-Like Receptor Subfamily B, CpG Oligodeoxynucleotide, medicine.drug_class, Cell Survival, Immunology, Brain tumor, Biology, Monoclonal antibody, CpG-ODN, Antibodies, Immune system, Adjuvants, Immunologic, Cell Line, Tumor, medicine, Animals, Memory Disorders, Pathogen-associated molecular pattern, Interleukin-2 Receptor alpha Subunit, Immunotherapy, medicine.disease, Antineoplastic Agents, Phytogenic, Mice, Inbred C57BL, Disease Models, Animal, Toll-Like Receptor 9, Neurology (clinical), Neoplasm Transplantation, CNS tumor
Abstract

International audience; Using brain lymphoma model, we demonstrate that immunotherapy combining Treg depletion (using anti-CD25 mAb PC61) followed by intracranial CpG-ODN administration induced tumor rejection in all treated mice and led to the establishment of a memory antitumor immune response in 60% of them. This protective effect was associated with a recruitment of NK cells and, to a lesser extent, of dendritic cells, B cells and T lymphocytes. NK cell depletion abolished the protective effect of the treatment, confirming a major role of NK cells in brain tumor elimination. Each treatment used alone failed to protect brain tumor bearing mice, revealing the therapeutic benefit of combining Treg depletion and local CpG-ODN injection.

Published
2014
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24. Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

Author

Myriam Robard, Claire Pecqueur, Marc Bonneville, Emmanuel Scotet, Sandrine Minault, Noémie Joalland, Henri Vié, François M. Vallette, Cynthia Chauvin, Ulrich Jarry, Alexandra Léger, Lisa Oliver, Bernardo, Elizabeth, BLANC - Détection du stress cellulaire par les lymphocytes T gamma/delta humains - - GDSTRESS2012 - ANR-12-BSV3-0024 - BLANC - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme MicroPicel, Université de Nantes (UN), This work has been supported by INSERM, CNRS, Université de Nantes, Association pour la Recherche contre le Cancer (#R10139NN), Institut National du Cancer (#V9V2THER, INCa #PLBio2013-201, #PLBio2014-155), Agence Nationale de la Recherche (ANR, #GDSTRESS),LigueNationalecontreleCancer(AOInterRegional2012)., ANR-12-BSV3-0024,GDSTRESS,Détection du stress cellulaire par les lymphocytes T gamma/delta humains(2012), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), and ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010)

Subjects
0301 basic medicine, human glioblastoma, Adoptive cell transfer, Pathology, medicine.medical_specialty, medicine.medical_treatment, T cell, Immunology, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Aminobisphosphonate, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Parenchyma, medicine, Immunology and Allergy, mice model, Original Research, business.industry, Vgamma9Vdelta2Tcells, Immunotherapy, medicine.disease, Peripheral blood, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, T cell subset, immunotherapy, business, Glioblastoma
Abstract

International audience; Glioblastoma multiforme (GBM) represents the most frequent and deadliest primary brain tumor.Aggressive treatment still fails to eliminate deep brain infiltrative and highly resistant tumor cells.Human Vg9Vd2 T cells, the major peripheral blood gd T cell subset, react against a wide array oftumor cells and represent attractive immune effector T cells for the design of antitumor therapies.This study aims at providing a preclinical rationale for immunotherapies in GBM based on stereotaxicadministration of allogeneic human Vg9Vd2 T cells. The feasibility and the antitumor efficacy ofstereotaxic Vg9Vd2 T cell injections have been investigated in orthotopic GBM mice model usingselected heterogeneous and invasive primary human GBM cells. Allogeneic human Vg9Vd2 T cellssurvive and patrol for several days within the brain parenchyma following adoptive transfer and cansuccessfully eliminate infiltrative GBM primary cells. These striking observations pave the way foroptimized stereotaxic antitumor immunotherapies targeting human allogeneic Vg9Vd2 T cells in GBMpatients.

Published
2016
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25. Efficiently stimulated adult microglia cross-prime naive CD8+ T cells injected in the brain

Author

Ulrich, Jarry, Pascale, Jeannin, Laurent, Pineau, Sabrina, Donnou, Yves, Delneste, and Dominique, Couez

Subjects
Mice, Inbred C57BL, Antigen Presentation, Mice, Cross-Priming, Solubility, Gamma Rays, Animals, Antigen-Presenting Cells, Brain, Microglia, Antigens, CD8-Positive T-Lymphocytes, Injections, Intraventricular
Abstract

Microglia are the major myeloid-immune cells of the brain parenchyma. In a steady state, microglia monitor their environment for pathogens or damaged cells. In response to neural injury or inflammation, microglia become competent APCs able to prime CD4(+) and CD8(+) T lymphocytes. We previously demonstrated that neonatal and adult microglia cross-present exogenous soluble Ags in vitro. However, whether microglia are able to cross-present Ag to naive CD8(+) T cells in vivo, within the brain microenvironment, remains undetermined. Here, we have designed an original protocol in order to exclude the involvement in cross-presentation activity of peripheral migrating APCs and of CNS-associated APCs. In C57Bl/6 mice, in which the body but not the head has been properly irradiated, we analyzed the ability of resident microglia to stimulate intracerebrally injected CD8(+) T cells in vivo. This study demonstrates for the first time that adult microglia cross-present Ag to naive CD8(+) T cells in vivo and that full microglia activation is required to overcome the inhibitory constrains of the brain and to render microglia able to cross-prime naive CD8(+) T cells injected in the brain. These observations offer new insights in brain-tumor immunotherapy based on the induction of cytotoxic antitumoral T cells.

Published
2012

26. The scavenger receptors SRA-1 and SREC-I cooperate with TLR2 in the recognition of the hepatitis C virus non-structural protein 3 by dendritic cells

Author

Vincenzo Barnaba, Simon Blanchard, Mari Scotet, Céline Beauvillain, Ulrich Jarry, Jean-Claude Sirard, Giovanni Magistrelli, Francesca Meloni, Pascale Jeannin, Yves Delneste, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Immunologie et d'Allergologie [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Interactions cellulaires et moléculaires des bactéries pathogènes avec l'hôte, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Novimmune SA, This work was supported by institutional grants from Inserm and University of Angers and by grants from the Ligue contre le Cancer (équipe labellisée 2008–2010 and Comité départemental du Maine et Loire), Cancéropole Grand-Ouest and Région Pays de la Loire (project CIMATH). U.J. received a grant from the Association pour la Recherche contre le Cancer., and Sirard, Jean-Claude

Subjects
viruses, Endocytic cycle, Lipopolysaccharide Receptors, MESH: Cricetinae, Hepacivirus, Plasmacytoid dendritic cell, Viral Nonstructural Proteins, MESH: Monocytes, Monocytes, MESH: Recombinant Proteins, Mice, Scavenger receptors, 0302 clinical medicine, MESH: Cricetulus, Interferon, Cricetinae, TLR2, Myeloid Cells, MESH: Animals, MESH: Hepacivirus, Receptors, Scavenger, 0303 health sciences, Toll-like receptor, MESH: Dendritic Cells, MESH: Antigens, CD14, MESH: Bone Marrow Cells, virus diseases, MESH: Toll-Like Receptor 2, Cell Differentiation, Vaccine vector, cooperation between innate receptors, cross-presentation, hcv ns3, scavenger receptors, tlr2, vaccine vector, Endocytosis, Recombinant Proteins, Scavenger Receptors, Class F, 3. Good health, Cell biology, Biochemistry, MESH: Endocytosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug, MESH: Cell Differentiation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Bone Marrow Cells, CHO Cells, Biology, Transfection, 03 medical and health sciences, Cricetulus, MESH: CHO Cells, parasitic diseases, medicine, Animals, Humans, Cooperation between innate receptors, MESH: Receptors, Scavenger, Scavenger receptor, Antigen-presenting cell, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Adaptor Proteins, Signal Transducing, Cross-presentation, MESH: Humans, MESH: Scavenger Receptors, Class F, Hepatology, MESH: Transfection, Dendritic Cells, Dendritic cell, biochemical phenomena, metabolism, and nutrition, MESH: Myeloid Cells, Toll-Like Receptor 2, digestive system diseases, HCV NS3, MESH: Viral Nonstructural Proteins, 030215 immunology
Abstract

International audience; BACKGROUNDS & AIMS: The hepatitis C virus NS3 protein is taken up by myeloid cells in a TLR2-independent manner and activates myeloid cells via TLR2. This study aimed to identify the endocytic receptor(s) involved in the uptake of NS3 by myeloid cells and its relation with TLR2. METHODS: Inhibitors and transfected cells were used to identify the nature of the NS3-binding receptors expressed by myeloid cells. The cooperation between scavenger receptors (SRs) and TLR2 in the NS3-mediated activation of myeloid cells was evaluated using inhibitors, cells from TLR2(-/-) mice, and confocal microscopy. The involvement of SRs in NS3 cross-presentation was evaluated in vitro using an NS3-specific human T-cell clone. RESULTS: We observed that SRs are the main binding structures for NS3 on myeloid cells and identified the SRs SRA-1 and SREC-I as endocytic receptors for NS3. Moreover, both SRs and TLR2 cooperate in NS3-induced myeloid cell activation. CONCLUSION: This study highlights a central role for SRs in NS3 uptake and cross-presentation, and demonstrates a tightly orchestrated cooperation between signalling and endocytic innate receptors in NS3 recognition.

Published
2010
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