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29 results on '"Cédric Ménard"'

1. Lenalidomide triggers T-cell effector functions in vivo in patients with follicular lymphoma

Author

Nadège Bescher, Maelle Latour, Roch Houot, Isabelle Bezier, Joelle Dulong, Myriam Chouteau, Delphine Rossille, Thierry Fest, Cédric Ménard, Karin Tarte, Ilenia Papa, Franck Morschhauser, Tien-Tuan Nguyen, CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), CHU Lille, Jonchère, Laurent, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )

Subjects
obinutuzumab, Lymphoma, B-Cell, Immunobiology and Immunotherapy, T cell, lenalidomide, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunomodulation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, follicular lymphoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Obinutuzumab, In vivo, medicine, Humans, Lymphoma, Follicular, t-lymphocytes, B cell, 030304 developmental biology, Lenalidomide, 0303 health sciences, Lymphoid Neoplasia, business.industry, Hematology, medicine.disease, 3. Good health, Lymphoma, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer research, business, Ex vivo, medicine.drug
Abstract

The immunomodulatory drug lenalidomide is used in patients with follicular lymphoma (FL) with the aim of stimulating T-cell antitumor immune response. However, little is known about the effects of lenalidomide on T-cell biology in vivo in patients with FL. We thus undertook an extensive longitudinal immunologic study, including phenotypic, transcriptomic, and functional analyses, on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial (Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL. Lenalidomide rapidly and transiently induced an activated T-cell phenotype, including HLA-DR, Tim-3, CD137, and programmed cell death protein 1 (PD-1) upregulation. Furthermore, sequential RNA-sequencing of sorted PD-1+ and PD-1– T-cell subsets revealed that lenalidomide triggered a strong enrichment for several gene signatures related to effector memory T-cell features, including proliferation, antigen receptor signaling, and immune synapse restoration; all were validated at the phenotypic level and with ex vivo functional assays. Correlative analyses pinpointed a negative clinical impact of high effector T-cell and regulatory T-cell percentages before and during treatment. Our findings bring new insight in lenalidomide mechanisms of action at work in vivo and will fuel a new rationale for the design of combination therapies.

Published
2021
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2. Immunomonitoring et thérapie cellulaire : l’exemple des patients traités par cellules stromales mésenchymateuses

Author

Cédric Ménard

Subjects
0301 basic medicine, 03 medical and health sciences, Medical Laboratory Technology, 030104 developmental biology, Biochemistry (medical), Analytical Chemistry
Abstract

Resume Les proprietes immunomodulatrices et anti-inflammatoires des cellules stromales mesenchymateuses sont la base de nombreux essais cliniques dans le monde entier. Un probleme majeur au developpement de cette therapie cellulaire est l’incapacite de predire la reponse ou l’echappement a ce type de traitement couteux. Grâce a l’utilisation combinee de techniques d’analyses transcriptomiques, proteomiques ou fonctionnelles menees sur du sang voire des biopsies tissulaires, il est possible de monitorer aux differentes etapes du traitement les modifications induites par la therapie sur une grande palette de parametres immunologiques. Ce type d’immunomonitoring pousse et standardise permettra, en lien avec l’analyse de la reponse clinique, de degager des biomarqueurs d’efficacite pertinents.

Published
2018
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3. Integrated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Properties of Mesenchymal Stromal Cells

Author

Philippe Collas, Nadège Bescher, Erwan Flecher, Karin Tarte, Joelle Dulong, Benjamin Hébraud, David Roulois, Louis Casteilla, Céline Monvoisin, Léa Verdière, Mélanie Gadelorge, Céline Pangault, Cédric Ménard, Vonick Sibut, Luc Sensebé, Philippe Bourin, Nicolas Espagnolle, Nicolas Bertheuil, Isabelle Bezier, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang [Rennes] (EFS Bretagne), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Microenvironnement et cancer (MiCa), Recherches Avicoles (SRA), Institut National de la Recherche Agronomique (INRA), Laboratoire de Thérapie Cellulaire, EFS, Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut d'Electronique et de Télécommunications de Rennes (IETR), 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)-SUPELEC-Centre National de la Recherche Scientifique (CNRS), STROMALab, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Akershus University Hospital [Lørenskog], Laboratoire de thérapie cellulaire (EFS), Etablissement Français du Sang, ANR-10-IBHU_0005, Agence Nationale de la Recherche, APR 2016, Etablissement Français du Sang, INCa PLBIO-17-219, Institut National Du Cancer, Appel d'offre local 2008, CHU Toulouse, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], Centre National de la Recherche Scientifique (CNRS)-Ecole Supérieure d'Electricité - SUPELEC (FRANCE)-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)-Université de Rennes (UNIV-RENNES)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-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 ), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Supérieure d'Electricité - SUPELEC (FRANCE)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Ménard, Cédric, 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, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Karin, UMR U1236 MICMAC, Cell, Philippe, Adipose tissue, 0302 clinical medicine, Gene expression, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, INSERM, Bone marrow stromal cells (BMSCs), Etablissement Français du Sang, CSA21, Cell Differentiation, Middle Aged, Phenotype, Immunogenicity, Cell interactions Journal Section: Translational and Clinical Research Cell Types: Bone Marrow Stem Cells, Cell biology, medicine.anatomical_structure, CHU Rennes Keywords: adipose stem cells, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, STROMALAB Tarte, Adult, Stromal cell, Nicolas, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adipose Stem Cells/VSF, Biology, Young Adult, 03 medical and health sciences, Immune system, medicine, Humans, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, Direction Espagnolle, Université Rennes 1, 030104 developmental biology, SITI Laboratory, Bone marrow, Transcriptome, 030217 neurology & neurosurgery, Immunosuppression, Developmental Biology
Abstract

Clinical-grade mesenchymal stromal cells (MSCs) can be expanded from bone marrow and adipose tissue to treat inflammatory diseases and degenerative disorders. However, the influence of their tissue of origin on their functional properties, including their immunosuppressive activity, remains unsolved. In this study, we produced paired bone marrow-derived mesenchymal stromal cell (BM-MSC) and adipose-derived stromal cell (ASC) batches from 14 healthy donors. We then compared them using transcriptomic, phenotypic, and functional analyses and validated our results on purified native MSCs to infer which differences were really endowed by tissue of origin. Cultured MSCs segregated together owing to their tissue of origin based on their gene expression profile analyzed using differential expression and weighted gene coexpression network analysis. This translated into distinct immune-related gene signatures, phenotypes, and functional cell interactions. Importantly, sorted native BM-MSCs and ASCs essentially displayed the same distinctive patterns than their in vitro-expanded counterparts. As a whole, ASCs exhibited an immune profile consistent with a stronger inhibition of immune response and a lower immunogenicity, supporting the use of adipose tissue as a valuable source for clinical applications.

Published
2020
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4. Pulmonary alveolar proteinosis

Author

Mathieu Lederlin, Cédric Ménard, Stéphane Jouneau, Jonchère, Laurent, CHU Pontchaillou [Rennes], 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 ), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-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 )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, pulmonary alveolar proteinosis, Cryptococcus, Lung biopsy, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, rituximab, Internal medicine, Humans, Medicine, 030212 general & internal medicine, Lung, [SDV.IB] Life Sciences [q-bio]/Bioengineering, biology, Inhalation, business.industry, whole lung lavage, Nocardia, biology.organism_classification, medicine.disease, female genital diseases and pregnancy complications, infection, 3. Good health, 030228 respiratory system, granulocyte-macrophage colony-stimulating factor, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Rituximab, Plasmapheresis, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Tomography, X-Ray Computed, business, Pulmonary alveolar proteinosis, Actinomyces, medicine.drug
Abstract

International audience; PAP is an ultra-rare disease in which surfactant components, that impair gas exchange, accumulate in the alveolae. There are three types of PAP. The most frequent form, primary PAP, includes autoimmune PAP which accounts for over 90% of all PAP, defined by the presence of circulating anti-GM-CSF antibodies. Secondary PAP is mainly due to haematological disease, infections or inhaling toxic substances, while genetic PAP affects almost exclusively children. PAP is suspected if investigation for ILD reveals a crazy-paving pattern on chest CT scan, and is confirmed by a milky looking BAL that gives a positive PAS reaction indicating extracellular proteinaceous material. PAP is now rarely confirmed by surgical lung biopsy. WLL is still the first-line treatment, with an inhaled GM-CSF as second-line treatment. Inhalation has been found to be better than subcutaneous injections. Other treatments, such as rituximab or plasmapheresis, seem to be less efficient or ineffective. The main complications of PAP are due to infections by standard pathogens (Streptococcus, Haemophilus and Enterobacteria) or opportunistic pathogens such as mycobacteria, Nocardia, Actinomyces, Aspergillus or Cryptococcus. The clinical course of PAP is unpredictable and spontaneous improvement can occur. The 5-year actuarial survival rate is 95%.

Published
2020
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5. Adipose mesenchymal stromal cells Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery

Author

Benoit Chaput, Eric Watier, Cédric Ménard, Audrey Varin, Karin Tarte, Jérôme Laloze, Nicolas Bertheuil, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier

Subjects
medicine.medical_specialty, Adipose stromal cells, Nanofat grafting, Adipose tissue, Tissu adipeux, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030230 surgery, Mesenchymal Stem Cell Transplantation, Regenerative Medicine, Regenerative medicine, Immunomodulation, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fat grafting, Humans, Medicine, business.industry, Mesenchymal stem cell, Mesenchymal Stem Cells, Immunomodulatory properties, Stromal vascular fraction, Clinical routine, Adipose stem cells, 3. Good health, Plastic surgery, Adipose Tissue, Cellules souches, Cancer research, Surgery, business, Cellules stromales mésenchymateuses du tissu adipeux
Abstract

International audience; Ever since their discovery in 2001, adipose mesenchymal stromal cells (ASC) have profoundly modified clinical indications and our practice of plastic surgery, thereby placing our discipline at the forefront of regenerative medicine. These cells act through paracrine signaling by synthesizing immunosuppressive and pro-angiogenic factors. They are of key importance with regard to the regenerative properties of autologously grafted adipose tissue (AT). Taken together, they make up the stromal vascular fraction (SVF) comprising all AT cells except for adipocytes. As our knowledge evolves, we are moving from fat grafting towards SVF grafting, of which the essential sought-after effect is tissue regeneration. The objective of the present review is to synthesize present-day information on ASCs and their immunomodulatory properties and, from a practical standpoint, to indicate present-day and future steps towards establishment of clinical routine, particularly through application of techniques favoring mechanical digestion of adipose tissue.

Published
2019
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6. Biomarqueurs prédictifs de réponse aux inhibiteurs de points de contrôle immuns [Predictive biomarkers of response to immune checkpoint inhibitors.]

Author

Alexandra Lespagnol, Cédric Ménard, Romain Corre, Karin Tarte, Samuel Le Sourd, Jean Mosser, Marc Pracht, Julien Edeline, Alexandra Frelau, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], CRLCC Eugène Marquis (CRLCC), 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), CRLCC Eugène Marquis ( CRLCC ), Microenvironnement et cancer ( MiCa ), 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 ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, Université de Rennes (UR)-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 ), 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 ), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'oncologie médicale, Molecular Engines Laboratories (MEL), Molecular Engines Laboratories, Microenvironnement et cancer (MiCa), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Immunothérapie, [SDV.CAN]Life Sciences [q-bio]/Cancer, PD-L1 expression, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Biopsy, Medicine, Radiology, Nuclear Medicine and imaging, Neutrophil to lymphocyte ratio, ComputingMilieux_MISCELLANEOUS, Biomarqueurs, Anti-PD1, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, medicine.diagnostic_test, [ SDV ] Life Sciences [q-bio], business.industry, Hematology, General Medicine, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Expression de PD-L1, Primary tumor, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Biomarker (medicine), Antibody, business, PD-1 blockades, Biomarkers
Abstract

International audience; Les anti-PD-1 s’imposent dernièrement comme un traitement de référence dans de nombreux cancers métastatiques. Ils présentent l’avantage d’une efficacité significative doublée d’un profil de toxicité favorable en monothérapie. Les taux et durées de réponse sont toutefois très variables, ce qui implique, vu leur coût, d’identifier des biomarqueurs prédictifs de réponse. Dans cette revue de la littérature, nous nous intéressons aux biomarqueurs de réponse des immunothérapies anti-PD1 et anti-CTLA-4. L’expression de PD-L1 par les cellules tumorales et du micro-environnement évaluée par immunohistochimie est prédictive de réponse pour certains cancers mais reste une approche mal standardisée avec différents anticorps, différents seuils de positivité et différentes cibles (tumeur ou micro-environnement). Il s’agit aussi d’une expression dynamique au cours du temps et hétérogène donc souvent discordante entre biopsies et pièces opératoires. Les lymphocytes circulants pourraient représenter un biomarqueur prédictif notamment via la mesure du ratio polynucléaires neutrophiles sur lymphocytes (NLR), ratio simple à réaliser en pratique courante. Un taux de néoantigènes élevé serait également associé à une réponse plus importante ce qui expliquerait les taux de réponses particulièrement élevés des tumeurs avec instabilité micro-satellitaire. Des signatures génomiques pourraient également prédire la sensibilité aux anti-PD1. Par ailleurs, la présence de certaines bactéries de la flore intestinale favoriserait la réponse immunitaire antitumorale même si le mécanisme demeure mal compris. Enfin, des signatures d’expression de cytokines, médiatrices de la réponse immune, pourraient constituer des biomarqueurs pertinents. Plusieurs biomarqueurs de réponse potentiels semblent donc intéressants mais aucun n’est encore prospectivement validé à ce jour.

Published
2018
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7. An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma

Author

Franck Morschhauser, Hervé Tilly, Cédric Ménard, Bettina Fabiani, Roch Houot, Catherine Thieblemont, Krimo Bouabdallah, Karin Tarte, Gilles Salles, Steven Le Gouill, Guillaume Cartron, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)

Subjects
Adult, Male, medicine.medical_specialty, Lymphoma, B-Cell, Maximum Tolerated Dose, Clinical Trials and Observations, Immunology, Follicular lymphoma, Administration, Oral, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, Antibodies, Monoclonal, Humanized, Biochemistry, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Refractory, Obinutuzumab, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lenalidomide, Lymphoma, Follicular, Aged, Aged, 80 and over, business.industry, Cell Biology, Hematology, Middle Aged, medicine.disease, 3. Good health, Lymphoma, chemistry, 030220 oncology & carcinogenesis, Rituximab, Female, Neoplasm Recurrence, Local, business, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract

International audience; Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.

Published
2018
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8. NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment

Author

Franck Morschhauser, Cédric Ménard, Karin Tarte, Catherine Alexia, Dang-Nghiem Vo, Nerea Allende-Vega, Guillaume Cartron, Martin Villalba, Roch Houot, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Lapeyronie [Montpellier] (CHU), Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Bio_GALEN, GALEN study, DNV, Ministére de l'Enseignement Superior et de la Recherche France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Rennes (UR)-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 )

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, obinutuzumab, Immunology, Cell, lenalidomide, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, chemistry.chemical_compound, Obinutuzumab, medicine, Immunology and Allergy, Cytotoxic T cell, NK cell, Original Research, Lenalidomide, Antibody-dependent cell-mediated cytotoxicity, CD20, biology, business.industry, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Lymphoma, 030104 developmental biology, medicine.anatomical_structure, diffuse large B-cell lymphoma (DLBCL), Oncology, chemistry, follicular lymphoma (FL), biology.protein, Cancer research, Rituximab, business, lcsh:RC581-607, medicine.drug
Abstract

International audience; Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20 neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69, CD45RARO, CD107a, CD19) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.

Published
2018
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9. Liposuction Preserves the Morphological Integrity of the Microvascular Network: Flow Cytometry and Confocal Microscopy Evidence in a Controlled Study

Author

Cédric Ménard, Eric Watier, Benoit Chaput, Jean-Louis Grolleau, Frédéric Mourcin, Karin Tarte, Audrey Varin, Sandra Berger-Müller, Ignacio Garrido, Nicolas Bertheuil, Luc Sensebé, Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], EFS, Microenvironnement et cancer (MiCa), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement Français du Sang Bretagne, Service de Chirurgie Plastique, Chirurgie plastique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de Chirurgie Oncologique, Institut Claudius Regaud, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0005, European Center for Transplantation Sciences and Immunotherapy, Médaille d'or from Rennes University Hospital, ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Service de chirurgie plastique, reconstructive et esthétique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-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 ), Service Chirurgie plastique - brûlés [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, CD31, medicine.medical_specialty, Pathology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Urology, Adipose tissue, 030230 surgery, Flow cytometry, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Lipectomy, Confocal microscopy, law, Adipocyte, Adipocytes, medicine, Humans, Microscopy, Confocal, medicine.diagnostic_test, business.industry, Abdominoplasty, Endothelial Cells, General Medicine, Middle Aged, Flow Cytometry, Plastic surgery, Microvascular Network, Adipose Tissue, chemistry, 030220 oncology & carcinogenesis, Liposuction, Microvessels, Female, Surgery, business
Abstract

International audience; BACKGROUND: Liposuction is a very popular technique in plastic surgery that allows for the taking adipose tissue (AT) on large surfaces with little risk of morbidity. Although liposuction was previously shown to preserve large perforator vessels, little is known about the effects of liposuction on the microvasculature network. OBJECTIVES: The aim of this study was to analyze the effect of liposuction on the preservation of microvessels at tissue and cellular levels by flow cytometry and confocal microscopy following abdominoplasty procedure. METHODS: Percentage of endothelial cells in AT from liposuction and en bloc AT was determined by multicolor flow cytometry. Moreover, vessel density and adipocyte content were analyzed in situ in 3 different types of AT (en bloc, from liposuction, and residual AT after liposuction) by confocal microscopy. RESULTS: Flow cytometric analysis showed that en bloc AT contained 30.6% ± 12.9% and AT from liposuction 21.6% ± 9.9% of endothelial cells (CD31(pos)/CD45(neg)/CD235a(neg)/CD11b(neg)) (P = .009). Moreover, analysis of paired AT from the same patients (n = 5) confirmed a lower percentage of endothelial cells in AT from liposuction compared to en bloc AT (17.7% ± 4.5% vs 21.9% ± 3.3%, P = .031). Likewise, confocal microscopy showed that en bloc AT contained 8.2% ± 6.3%, AT from liposuction only 1.6% ± 1.0% (P \textless .0001), and AT after liposuction 8.9% ± 4.1% (P = .111) of CD31(pos) vessels. Conversely, adipocyte content was 39.5% ± 14.5% in the en bloc AT, 45% ± 18.4% in AT from liposuction (P = .390), and 18.8 ± 14.8% in AT after liposuction (P = .011). CONCLUSIONS: For the first time, we demonstrate that liposuction preserves the microvascular network. Indeed, a low percentage of endothelial cells was found in AT from liposuction and we confirm the persistence of microvessels in the tissue after liposuction

Published
2015
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10. WITHDRAWN: Biomarqueurs prédictifs de réponse aux inhibiteurs de points de contrôle immuns

Author

Marc Pracht, Alexandra Lespagnol, Julien Edeline, Cédric Ménard, Samuel Le Sourd, Jean Mosser, Karin Tarte, Romain Corre, and Alexandra Frelau

Subjects
Gynecology, 0303 health sciences, Cancer Research, medicine.medical_specialty, business.industry, Hematology, General Medicine, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Medicine, Radiology, Nuclear Medicine and imaging, business, 030304 developmental biology
Published
2018
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11. Proteasomal Indoleamine 2,3-Dioxygenase Degradation Reduces the Immunosuppressive Potential of Clinical Grade-Mesenchymal Stromal Cells Undergoing Replicative Senescence

Author

Rémy Pedeux, Nadine Mézière, Maelle Latour, Cédric Ménard, Joelle Dulong, Bezier Isabelle, Luc Sensebe, Séverine Loisel, Nicolas Bertheuil, Erwan Flecher, Karin Tarte, Marie-Laure Renoud, Nadège Bescher, Etablissement français du sang [Rennes] (EFS Bretagne), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Pyrénées-Méditerranée] (EFS Pyrénées-Méditerranée), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], Funded by Agence Nationale de la Recherche. Grant Number: ANR-11-RPIB-0012, Etablissement Français du Sang. Grant Number: APR 2016, Infrastructure program EcellFRANCE. Grant Number: ANR-11-INSB-005, European Center for Transplantation Sciences and Immunotherapy. Grant Number: IHU CESTI, ANR-10-IBHU_0005, ANR-11-RPIB-0012,SAFE,Production sécurisée de Cellules stromales du tissu adipeux pour la thérapie cellulaire(2011), Etablissement Français du Sang Pyrénées Méditerranée (EFS), CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), 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), Service de chirurgie plastique, reconstructive et esthétique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-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 ), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Senescence, Proteasome Endopeptidase Complex, T-Lymphocytes, T cells, Adipose tissue, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MG132, medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Indoleamine 2,3-dioxygenase, Cellular Senescence, Cell Proliferation, Immunosuppression Therapy, Clinical translation, Mesenchymal stem cell, Bone marrow stromal cells, Cell Biology, Adipose stem cells, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Proteolysis, Immunology, Proteasome inhibitor, Cancer research, Molecular Medicine, Mesenchymal stem cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, Immunosuppression, Developmental Biology, medicine.drug
Abstract

Owing to their immunosuppressive properties, mesenchymal stromal cells (MSCs) obtained from bone marrow (BM-MSCs) or adipose tissue (ASCs) are considered a promising tool for cell therapy. However, important issues should be considered to ensure the reproducible production of efficient and safe clinical-grade MSCs. In particular, high expansion rate, associated with progressive senescence, was recently proposed as one of the parameters that could alter MSC functionality. In this study, we directly address the consequences of replicative senescence on BM-MSC and ASC immunomodulatory properties. We demonstrate that MSCs produced according to GMP procedures inhibit less efficiently T-cell, but not Natural Killer (NK)- and B-cell, proliferation after reaching senescence. Senescence-related loss-of-function is associated with a decreased indoleamine 2,3-dioxygenase (IDO) activity in response to inflammatory stimuli. In particular, although STAT-1-dependent IDO expression is transcriptionally induced at a similar level in senescent and nonsenescent MSCs, IDO protein is specifically degraded by the proteasome in senescent ASCs and BM-MSCs, a process that could be reversed by the MG132 proteasome inhibitor. These data encourage the use of appropriate quality controls focusing on immunosuppressive mechanisms before translating clinical-grade MSCs in the clinic.

Published
2017
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12. Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Author

Cédric Ménard, Jonathan M. Irish, Karin Tarte, Thierry Fest, Mikael Roussel, Faustine Lhomme, Jonchère, Laurent, Etablissement français du sang [Rennes] (EFS Bretagne), Service d’immunologie, de thérapie cellulaire et d’hématopoïèse, Hôpital Pontchaillou, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), Vanderbilt University School of Medicine [Nashville], CHU Pontchaillou [Rennes], This work was supported by a research grant from the National Institute of Cancer (INCa Recherche Translationnelle 2010), Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS), LYSA group (Lymphoma Study Association), Comité pour la Recherche Clinique et Translationnelle (CORECT, CHU Rennes), Ligue Nationale Contre le Cancer, R00 CA143231-03, the Vanderbilt-Ingram Cancer Center (VICC, P30 CA68485), VICC Ambassadors, and a VICC Hematology Helping Hands award., Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )

Subjects
0301 basic medicine, Cancer Research, Lymphoma, B-Cell, Myeloid, [SDV.IMM] Life Sciences [q-bio]/Immunology, Carcinogenesis, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor-associated macrophage, Biology, Immunomodulation, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Regulatory myeloid suppressor cells, medicine, Myeloid-derived suppressor cell, Animals, Humans, Immunology and Allergy, B-cell lymphoma, B cell, Tumor microenvironment, Myeloid-Derived Suppressor Cells, Germinal center, Germinal Center, medicine.disease, 3. Good health, Lymphoma, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Oncology, Myeloid-derived Suppressor Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor Escape, Mass cytometry
Abstract

International audience; In lymphomas arising from the germinal center, prognostic factors are linked to the myeloid compartment. In particular, high circulating monocyte or myeloid-derived suppressor cell counts are associated with poor prognosis for patients with high-grade B-cell lymphomas. Macrophages with an M2 phenotype are enriched within lymphoma tumors. However, the M1/M2 nomenclature is now deprecated and the clinical impact of this phenotype remains controversial. Across cancer types, myeloid cells are primarily thought to function as immune suppressors during tumor initiation and maintenance, but the biological mechanisms behind the myeloid signatures are still poorly understood in germinal center B-cell lymphomas. Herein, we describe the role and clinical relevance of myeloid cells in B-cell lymphoma and propose innovative approaches to decipher this complex cellular compartment. Indeed, characterization of this heterogeneous cell ecosystem has been largely accomplished with "low-resolution" approaches like morphological evaluation and immunohistochemistry, where cells are characterized using a few proteins and qualitative metrics. High-resolution, quantitative approaches, such as mass cytometry, are valuable to better understand myeloid cell diversity, functions, and to identify potential targets for novel therapies.

Published
2017
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13. Labeling of mesenchymal stromal cells with iron oxide–poly(l-lactide) nanoparticles for magnetic resonance imaging: uptake, persistence, effects on cellular function and magnetic resonance imaging properties

Author

Markus Rojewski, Cédric Ménard, Volker Rasche, Markus Urban, Natalie Fekete, Hubert Schrezenmeier, Gerlinde Schmidtke-Schrezenmeier, Erika Deak, Anna Musyanovych, Karin Tarte, Volker Mailänder, and Katharina Landfester

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Injections, Subcutaneous, Immunology, Endosomes, Biology, Mesenchymal Stem Cell Transplantation, Endocytosis, Ferric Compounds, Regenerative medicine, Dioxanes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, medicine, Animals, Humans, Immunology and Allergy, Rats, Wistar, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Transplantation, Staining and Labeling, medicine.diagnostic_test, Mesenchymal stem cell, Mesenchymal Stem Cells, Magnetic resonance imaging, Cell Biology, Magnetic Resonance Imaging, Rats, 3. Good health, Radiography, Oncology, chemistry, 030220 oncology & carcinogenesis, Biophysics, Feasibility Studies, Nanoparticles, Agarose, Original Article, Intracellular, Stem Cell Transplantation, Homing (hematopoietic)
Abstract

Background aims. Mesenchymal stromal cells (MSC) are the focus of research in regenerative medicine aiming at the regulatory approval of these cells for specific indications. To cope with the regulatory requirements for somatic cell therapy, novel approaches that do not interfere with the natural behavior of the cells are necessary. In this context in vivo magnetic resonance imaging (MRI) of labeled MSC could be an appropriate tool. Cell labeling for MRI with a variety of different iron oxide preparations is frequently published. However, most publications lack a comprehensive assessment of the noninterference of the contrast agent with the functionality of the labeled MSC, which is a prerequisite for the validity of cell-tracking via MRI. Methods.We studied the effects of iron oxide-poly(L-lactide) nanoparticles in MSC with flow cytom-etry, transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), Prussian blue staining, CyQuant® proliferation testing, colony-forming unit-fibroblast (CFU-F) assays, flow chamber adhesion testing, immuno-logic tests and differentiation tests. Furthermore iron-labeled MSC were studied by MRI in agarose phantoms and Wistar rats. Results. It could be demonstrated that MSC show rapid uptake of nanoparticles and long-lasting intracellular persistence in the endosomal compartment. Labeling of the MSC with these particles has no influence on viability, differentiation, clonogenicity, proliferation, adhesion, phenotype and immunosuppressive properties. They show excellent MRI properties in agarose phantoms and after subcutaneous implantation in rats over several weeks. Conclusions. These particles qualify for studying MSC homing and trafficking via MRI.

Published
2011
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14. Les cellules stromales mésenchymateuses du tissu adipeux : historique, isolement, propriétés immunomodulatrices et perspectives cliniques [Adipose-derived stromal cells: History, isolation, immunomodulatory properties and clinical perspectives]

Author

Benoit Chaput, Ignacio Garrido, J L Grolleau, Karin Tarte, Nicolas Bertheuil, Eric Watier, Luc Sensebé, Audrey Varin, Cédric Ménard, Service de chirurgie plastique, reconstructive et esthétique [Rennes] = Cosmetic Reconstructive and Plastic surgery [Rennes], CHU Pontchaillou [Rennes], STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et cancer (MiCa), Université de Rennes (UR)-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 ), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de chirurgie plastique, reconstructive et esthétique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)

Subjects
Stromal cell, Stromal vascular fraction, [SDV]Life Sciences [q-bio], Mesenchymal stromal cells, Regenerative medicine, Fraction vasculaire stromale, Cell therapy, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, In vivo, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cellules stromales mésenchymateuses, Propriétés anti-inflammatoires, 0303 health sciences, business.industry, Mesenchymal stem cell, Anti-inflammatory effect, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Surgery, Bone marrow, Stem cell, business, Médecine régénérative, Immunosuppression
Abstract

Over the last decade, the clinical use of adipose-derived stromal/stem cells (ASC) in regenerative medicine is rapidly increasing. ASC belong to the mesenchymal stromal cells initially obtained from the bone marrow. Their limited differentiation capacity in vivo into functional mature cells has led to a reassessment of their mechanisms of action. One of the major clinical interests appears related to paracrine effects through a temporary production of trophic and immunomodulatory factors. Our purpose is to provide a review on the latest knowledge in the field of ASC, mechanisms of action, mainly immunomodulatory/immunosuppressive properties, methods of obtention, with a focus on clinical perspectives particularly in the field of cellular therapy and fat grafting technique in plastic surgery.

Published
2015
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16. Lenalidomide Treatment Restores In Vivo T Cell Activity in Relapsed/Refractory FL and DLBCL

Author

Tien Tuan Nguyen, Isabelle Bezier, Roch Houot, Thierry Lamy, Maelle Latour, Cédric Ménard, Nadège Bescher, Joelle Dulong, Franck Morschhauser, Séverine Loisel, and Karin Tarte

Subjects
Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Immunology, Context (language use), Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Obinutuzumab, Internal medicine, medicine, Multiple myeloma, Lenalidomide, CD20, biology, business.industry, Cell Biology, Hematology, medicine.disease, chemistry, 030220 oncology & carcinogenesis, biology.protein, Rituximab, business, Diffuse large B-cell lymphoma, 030215 immunology, medicine.drug
Abstract

The immunostimulatory properties of lenalidomide have been mostly described in vitro while in vivo studies performed in multiple myeloma or chronic lymphocytic leukemia have reported a poorly characterized T-cell activation. A better understanding of lenalidomide kinetics and mechanisms of action is mandatory to optimize its combination with other immunotherapeutic agents in particular for the treatment of non Hodgkin lymphomas. We undertook a thorough immune monitoring of patients enrolled in the French multicenter clinical trial GALEN (ClinicalTrials.gov: NCT01582776) addressing the tolerance and efficacy of the association of lenalidomide and obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody, in relapsed/refractory B-cell lymphomas. A 1-week interval between the start of lenalidomide and the first infusion of obinutuzumab was planned, allowing an assessment of the effect of lenalidomide alone on immune-related parameters separately from the combinatorial therapy. Serial blood samples were collected in 44 patients (16 DLBCL and 28 FL) to investigate T, B, NK, and myeloid subsets. In addition, in vitro functional assays were designed to address T cell functional features (proliferation, immune synapse, activity of regulatory T cells (Treg)). In the context of the association with obinutuzumab, we first checked that CD20 expression was not affected on circulating malignant and normal B cells (p=0.43 and 0.8; respectively). Interestingly, upon 1 week of lenalidomide treatment, normal B cells, unlike malignant B cells, upregulated MHC class II (p We herein report for the first time early in vivo T cell activation by lenalidomide in relapse FL/DLBCL through a detailed phenotypic analysis strengthened by innovative functional assays. The study of T cells heterogeneity at the transcriptomic level is underway and the correlation of these immunomodulatory properties with clinical data is also currently being addressed. Our results will help build new and more relevant lenalidomide-based immunotherapeutic approaches. (This study was supported by research grants from Celgene and Roche companies) Disclosures Menard: Celgene: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Lamy: Roche: Consultancy, Honoraria. Morschhauser: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy; Gilead: Consultancy. Tarte: Celgene: Consultancy, Research Funding; Novimmune: Research Funding; Roche: Consultancy.

Published
2017
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17. EFFECTS OF A NOVEL CERAMIC BIOMATERIAL ON IMMUNE MODULATORY PROPERTIES AND DIFFERENTIATION POTENTIAL OF MESENCHYMAL STROMAL CELLS

Author

M. Di Trapani, Philippe Bourin, Markus Rojewski, Pierre Layrolle, Massimo Dominici, Rosaria Giordano, Giulio Bassi, Martina Midolo, Cédric Ménard, Roberta Carusone, Serge Baroth, Lorenza Lazzari, Fabien Guilloton, Luciano Pacelli, Karin Tarte, Luc Sensebe, Isabelle Bezier, Cristiana Lavazza, Mauro Krampera, Hubert Schrezenmeier, Frederic Deschaseaux, Eliana Amati, Stem Cell Research Laboratory, University of Verona (UNIVR), Microenvironnement et cancer (MiCa), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement Français du Sang Centre-Atlantique (EA3855), EFS, STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for transfusion medicine and Immunogenetic Clinics for Aplastic Anaemia, Ulm medical school, Institut für Transfusionsmedizin, Universität Ulm - Ulm University [Ulm, Allemagne], Institut für klinische Transfusionsmedizin und Immungenetik, DRK Blutspendedienst Baden-Württemberg—Hessen, Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Thérapie Cellulaire, Groupe d'Etude des Cellules Souches Mésenchymateuses (GECSOM), GECSOM, Università degli Studi di Verona, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Verona = University of Verona (UNIVR), Université de Rennes (UR)-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 ), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, medicine.medical_specialty, Immunology, Bone healing, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Research & Experimental Medicine, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, medicine, Immunology and Allergy, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Transplantation, Hematology, biology, Chemistry, Mesenchymal stem cell, Cell Biology, Cell biology, medicine.anatomical_structure, Oncology, Biotechnology & Applied Microbiology, 030220 oncology & carcinogenesis, Cord blood, Osteocalcin, biology.protein, Bone marrow
Abstract

International audience; The aim of this study was to assess the immune modulatory properties of human mesenchymal stromal cells obtained from bone marrow (BM-MSCs), fat (ASCs) and cord blood (CB-MSCs) in the presence of a novel hydroxyapatite and tricalcium-phosphate (HA/TCP) biomaterial as scaffold for MSC delivery. In resting conditions, a short-term culture with HA/TCP did not modulate the anti-apoptotic and suppressive features of the various MSC types towards T, B and NK cells; in addition, when primed with inflammatory cytokines, MSC maintained or not on HA/TCP similarlyincreased their suppressive capacities. The long-term culture of BM-MSCs with HA/TCP induced an osteoblast-like phenotype with up-regulation of OSTERIX and OSTEOCALCIN, similarly to what obtained with dexamethasone and, to a higher extent, BMP-4 treatment. MSC-derived osteoblasts did not trigger immune cell activation, but were less efficient than undifferentiated MSCs in inhibiting stimulated T and NK cells. Interestingly, their suppressive machinery included not only the activation of IDO, which plays a central role in T-cell inhibition, but also COX-2 that was not significantly involved in immune modulatory effect of human undifferentiated MSCs. COX-2 is significantly involved in bone healing, suggesting that its induction by HA/TCP could also contribute to the therapeutic activity of MSC for bone tissue engineering.

Published
2014
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18. Therapy-Induced Tumor Immunosurveillance Involves IFN-Producing Killer Dendritic Cells

Author

Mathieu Bonmort, Laurence Zitvogel, Evelyn Ullrich, Julien Taieb, Cédric Ménard, Guido Kroemer, Thomas Tursz, Grégoire Mignot, Nathalie Chaput, Sophie Viaud, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatogastro-entérologie et d'oncologie digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mignot, Grégoire

Subjects
Cancer Research, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunotherapy, MESH: Interferon-gamma, medicine.medical_treatment, MESH: Piperazines, Antineoplastic Agents, chemical and pharmacologic phenomena, Biology, Piperazines, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, MESH: Animals, Antigen-presenting cell, MESH: Mice, 030304 developmental biology, 0303 health sciences, Lymphokine-activated killer cell, Innate immune system, MESH: Dendritic Cells, Dendritic Cells, Neoplasms, Experimental, Immunotherapy, Dendritic cell, Natural killer T cell, 3. Good health, Immunosurveillance, Pyrimidines, MESH: Neoplasms, Experimental, Imatinib mesylate, Oncology, MESH: Pyrimidines, Benzamides, Immunology, Imatinib Mesylate, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology
Abstract

A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor–related apoptosis-inducing ligand–dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer. [Cancer Res 2007;67(3):851–3]

Published
2007
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19. Comparative study of immune regulatory properties of stem cells derived from different tissues

Author

Guido Francesco Fumagalli, Ilaria Decimo, Piero Anversa, P De Coppi, Luciano Pacelli, Emanuela Fontana, Karin Tarte, Francesco Bifari, M. Di Trapani, Luca Giacomello, Mario Ricciardi, Giulio Bassi, Mauro Krampera, Cédric Ménard, Francois Feron, Michela Pozzobon, Stem Cell Research Laboratory, University of Verona (UNIVR), Laboratory of Translation Surgery, Laboratory of Stem Cells and Regenerative Therapy, Universita degli Studi di Padova, CIC - Biotherapie - Marseille, Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Surgery, Hospital for Children, Harvard Medical School [Boston] (HMS), Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), Microenvironnement et cancer (MiCa), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire SITI, CHU Pontchaillou [Rennes]-Etablissement Français du Sange Bretagne, CARIVERONA, Bando 2008 e 2012, Italian Ministry of University and Scientific Research--PRIN 2009, Ricerca Sanitaria Finalizzata 2008, Gruppo Animazione Lesionati Midollari (GALM)--Verona, Federazione Associazioni Italiane Paratetraplegici (FAIP), 7th Framework Program of the European Commission: CASCADE (FP7-HEALTH-233236), REBORNE (FP7-HEALTH-241879), Università degli studi di Verona = University of Verona (UNIVR), Università degli Studi di Padova = University of Padua (Unipd), Université de Rennes (UR)-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 ), Università degli Studi di Verona, Department of Medicine and Public Health, and Le Corre, Morgane

Subjects
Cancer Research, Amniotic Fluid, Antigens, CD, Biomarkers, Bone Marrow Cells, Gene Expression, HLA Antigens, Humans, Immunophenotyping, Lymphocyte Subsets, Mesenchymal Stromal Cells, Cell Biology, 0302 clinical medicine, Meninges, Original Research Reports, Immunology and Allergy, Lung, Genetics (clinical), 0303 health sciences, integumentary system, Hematology, Intercellular Adhesion Molecule-1, Olfactory Bulb, 3. Good health, Cell biology, CD, Allogeneic stem cell (SC)-based therapy, Oncology, Organ Specificity, 030220 oncology & carcinogenesis, Stem cell, tissues, Adult stem cell, Immunology, Primary Cell Culture, Vascular Cell Adhesion Molecule-1, Human leukocyte antigen, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, adult stem cells, 03 medical and health sciences, Immune system, Antigen, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Indoleamine-Pyrrole 2,3,-Dioxygenase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antigens, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Transplantation, Myocardium, Mesenchymal stem cell, Mesenchymal Stem Cells, nervous system, Cell culture, Developmental Biology
Abstract

International audience; : Allogeneic stem cell (SC)-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some SC types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ectomesenchymal SCs, leptomeningeal SCs, and three different c-Kit-positive SC types, that is, amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers ICAM-1, VCAM-1, HLA-ABC, and HLA-DR, modulatory activity toward purified T, B, and NK cells, lower immunogenicity of inflammatory-primed SCs as compared to resting SCs, and indoleamine-2,3-dioxygenase-activation as molecular inhibitory pathways, with some SC type-related peculiarities. Moreover, the SC types analyzed exert an anti-apoptotic effect toward not-activated immune effector cells (IECs). In addition, we found that the inhibitory behavior is not a constitutive property of SCs, but is acquired as a consequence of IEC activation, as previously described for MSCs. Thus, immune regulation is a general property of SCs and the characterization of this phenomenon may be useful for a proper therapeutic use of SCs.

Published
2013
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20. Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls

Author

Isabelle Bezier, Hubert Schrezenmeier, Mauro Krampera, Maelle Latour, Cédric Ménard, Joelle Dulong, Karin Tarte, Francesco Bifari, Giulio Bassi, Philippe Bourin, Luciano Pacelli, Luc Sensebé, Jasmina Zanoncello, Mario Ricciardi, Microenvironnement et cancer (MiCa), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), Stem Cell Research Laboratory, Università degli Studi di Verona, STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Institut für Klinische Transfusionmedizin und Immungenetik, Universität Ulm - Ulm University [Ulm, Allemagne]-German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen, This work was supported by grants from the 7th Framework Program of the European Commission: CASCADE (FP7-HEALTH-233236) and REBORNE (FP7-HEALTH-241879) and by grants from the European Center for Transplantation Sciences and Immunotherapy (IHU CESTI, ANR-10-IBHU-0005)., European Project: 241879,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,REBORNE(2010), University of Verona (UNIVR), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-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 ), Università degli studi di Verona = University of Verona (UNIVR), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Ménard, Cédric, and Regenerating Bone defects using New biomedical Engineering approaches - REBORNE - - EC:FP7:HEALTH2010-01-01 - 2015-06-30 - 241879 - VALID

Subjects
Blood Platelets, Cell Extracts, Quality Control, Serum, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, T-Lymphocytes, Bone Marrow Cells, Biology, Proinflammatory cytokine, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, Original Research Reports, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Interferon gamma, 030304 developmental biology, Cell Proliferation, 0303 health sciences, B-Lymphocytes, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, Hematology, Coculture Techniques, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Adipose Tissue, Organ Specificity, 030220 oncology & carcinogenesis, Immunology, Cancer research, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Platelet lysate, Cattle, Bone marrow, Stem cell, Developmental Biology, medicine.drug
Abstract

International audience; Clinical-grade mesenchymal stromal cells (MSCs) are usually expanded from bone marrow (BMMSCs) or adipose tissue (ADSCs) using processes mainly differing in the use of fetal calf serum (FCS) or human platelet lysate (PL). We aimed to compare immune modulatory properties of clinical-grade MSCs using a combination of fully standardized in vitro assays. BMMSCs expanded with FCS (BMMSC-FCS) or PL (BMMSC-PL), and ADSC-PL were analyzed in quantitative phenotypic and functional experiments, including their capacity to inhibit the proliferation of T, B, and NK cells. The molecular mechanisms supporting T-cell inhibition were investigated. These parameters were also evaluated after pre-stimulation of MSCs with inflammatory cytokines. BMMSC-FCS, BMMSC-PL, and ADSC-PL displayed significant differences in expression of immunosuppressive and adhesion molecules. Standardized functional assays revealed that resting MSCs inhibited proliferation of T and NK cells, but not B cells. ADSC-PL were the most potent in inhibiting T-cell growth, a property ascribed to interferon-γ-dependent indoleamine 2,3-dioxygenase activity. MSCs did not stimulate allogeneic T cell proliferation but were efficiently lysed by activated NK cells. The systematic use of quantitative and reproducible validation techniques highlights differences in immunological properties of MSCs produced using various clinical-grade processes. ADSC-PL emerge as a promising candidate for future clinical trials.

Published
2013
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21. Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application

Author

Karin Tarte, Cédric Ménard, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-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 ), Etablissement Français du Sang Bretagne, EFS, Framework Program of the European Commission: CASCADE (FP7-HEALTH-233236), REBORNE (FP7-HEALTH-241879), the European Regional Development Fund (ERDF), the European Union, the European Center for Transplantation Sciences and Immunotherapy (IHU CESTI, ANR-10-IBHU-0005), Infrastructure Program ECELLFRANCE (ANR-11-INSB-005), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Corre, Morgane, 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, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )

Subjects
Chemokine, Stromal cell, Medicine (miscellaneous), [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mesenchymal Stem Cell Transplantation, Regenerative Medicine, immunomodulation, Biochemistry, Genetics and Molecular Biology (miscellaneous), Regenerative medicine, Cell therapy, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, mesenchymal stromal cells, immunomodulation, indoleamine 2, 3-dioxygenase, cell therapy, standardization, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, standardization, 0303 health sciences, biology, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, 3. Good health, 3-dioxygenase, Immune System Diseases, 030220 oncology & carcinogenesis, Immunology, biology.protein, Molecular Medicine, indoleamine 2, Stem cell, Chemokines, cell therapy, mesenchymal stromal cells
Abstract

International audience; Mesenchymal stromal cell (MSC)-based therapy holds great promise for treating immune disorders and for regenerative medicine in agreement with their paracrine trophic and immunosuppressive activities. Various processes have been developed worldwide to produce clinical grade MSCs but, so far, it is not known if one given MSC is more efficient than another. In addition, while their broad activity on innate and adaptative immune cell subsets is now widely admitted, the precise mechanisms supporting their immunoregulatory capacities are still a matter of debate. Finally, quantitative immunological potency assays correlated to clinical efficacy and clinically relevant immunomonitoring approaches for MSC-treated patients are sorely needed. Multiple parameters could influence the immunomodulatory potential of therapeutic MSCs. The most important challenge is now to differentiate, within a high number of poorly comparable and even contradictory pre-clinical studies, the parameters that could have some clinical impact from those that are only due to uncontrolled experimental variability. Importantly, besides MSC-related differences, primarily linked to production processes, several important variables associated with immune assays themselves, including selection of effector immune cells, activation signals, and read-out techniques, should be carefully considered to obtain solid results with potential therapeutic application. In this review, we establish a core of common and reproducible immunological properties of MSCs, shed light on technical issues concerning immunomodulatory potential assessment, and put them into perspective when considering clinical application.

Published
2013
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22. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes

Author

Olivier Fouquet, Gersende Caron, Fabien Guilloton, Joelle Dulong, Thierry Lamy, Patricia Amé-Thomas, Delphine Rossille, Cédric Ménard, John De Vos, Catherine Henry, Ceéline Pangault, Thierry Fest, Karin Tarte, Microenvironnement et cancer (MiCa), 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Modélisation Conceptuelle des Connaissances Biomédicales, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], INCa libre PL06-10, INCa PAIR Lymphome 2008-019, and Ligue Régionale Contre le Cancer

Subjects
Male, Cellular differentiation, Follicular lymphoma, MESH: Monocytes, Biochemistry, Monocytes, MESH: Lymphoma, Follicular, 0302 clinical medicine, Cell Movement, Lymphoma, Follicular, MESH: Cell Movement, Cells, Cultured, Chemokine CCL2, Oligonucleotide Array Sequence Analysis, MESH: Aged, B-Lymphocytes, 0303 health sciences, MESH: Middle Aged, MESH: Real-Time Polymerase Chain Reaction, Cell Polarity, Cell Differentiation, Hematology, Middle Aged, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Monocyte differentiation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Cell Polarity, MESH: Cells, Cultured, Adult, MESH: Cell Differentiation, Stromal cell, Blotting, Western, Immunology, Biology, CCL2, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: B-Lymphocytes, MESH: Cell Proliferation, Biomarkers, Tumor, medicine, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Chemokine CCL2, Aged, Cell Proliferation, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, Mesenchymal stem cell, Mesenchymal Stem Cells, MESH: Adult, Cell Biology, medicine.disease, MESH: Male, Lymphoma, MESH: Mesenchymal Stem Cells, MESH: Oligonucleotide Array Sequence Analysis, MESH: Tumor Markers, Biological, Cancer research, Bone marrow, Stromal Cells, MESH: Stromal Cells, MESH: Female
Abstract

Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.

Published
2012
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23. Immunosuppression et cellules souches mésenchymateuses Mieux comprendre une propriété thérapeutique majeure

Author

Karin Tarte, Cédric Ménard, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-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 ), programmes européens CASCADE et REBORNE du 7e Programme cadre de recherche et développement, Établissement français du sang, Agence de la biomédecine, Ligue contre le cancer, programme hospitalier de recherche clinique (PHRC 2005)., Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )

Subjects
MESH: Forecasting, 0303 health sciences, MESH: Humans, MESH: Immune Tolerance, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Biology, Molecular biology, MESH: Adaptation, Physiological, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, MESH: Mesenchymal Stem Cells, 030220 oncology & carcinogenesis, MESH: Animals, MESH: Mesenchymal Stem Cell Transplantation, 030304 developmental biology
Abstract

International audience; Since their efficiency to treat graft versus host disease has been proven, mesenchymal stem cells (MSC) represent a promising cell therapy approach for the treatment of immune disorders. In this context, much attention has focused on their mechanisms of action, in particular once the fact that their immune properties are also crucial for their efficiency in regenerative medicine was demonstrated. By their production of various and redundant soluble factors, MSC exert powerful anti-inflammatory and immunosuppressive effects targeting the main immune cell subsets. These immunoregulatory properties are essentially inducible by inflammatory mediators. In addition, it is now clear that allogeneic MSC are not immunoprivileged in immunocompetent recipient in agreement with their low persistence in vivo. They should thus display an early "touch-and-go" effect involving both direct interactions with recruited immune effectors and further amplification of this immunosuppression process through activation or conditioning of other regulatory immune cells. A better understanding of immunological properties of MSC will clearly improve their use in clinical settings.; Les cellules souches mésenchymateuses (CSM) possèdent des propriétés immunosuppressives très vastes liées à la production de facteurs solubles inductibles qui inhibent l'activation des principaux effecteurs de l'immunité. L'intérêt de ces propriétés a été confirmé dans des essais cliniques spectaculaires chez des patients atteints de la maladie du greffon contre l'hôte, une complication fréquente et grave des allogreffes de cellules souches hématopoïétiques. Depuis, les applications de ce potentiel anti-inflammatoire et immunosuppresseur des CSM ont été étendues à la médecine régénératrice puisque les capacités de réparation des CSM semblent étroitement liées à leurs propriétés immunologiques, démontrant tout l'intérêt d'une compréhension fine des interactions entre les CSM et les cellules immunitaires.

Published
2011
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24. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Author

Frédéric Commo, Sylvie Rusakiewicz, Jean Franãois Emile, Caroline Flament, Jean-Yves Blay, Nicolas Ibrahim, Véronique Minard-Colin, Saadia Kerdine-Römer, Philippe Terrier, Jacques A. Nunès, Cédric Ménard, Pascale Paul, Benedita Rocha, Laurence Zitvogel, Kariman Chaba, Alessandro Moretta, Dominique Valteau-Couanet, Cristina Bottino, Javier Celis Gutierrez, Luc Lyonnet, A. Lecesne, Nathalie Chaput, Stephan Roux, Hélène Authier, Jean Michel Coindre, Matthieu Sarabi, Pascal Rihet, Véronique Baud, Nicolas F. Delahaye, Laetitia Peaudecerf, Isabelle Martins, Sylvie Bonvalot, Jan Tavernier, Eric Vivier, Nicolas Isambert, Michaela Semeraro, Isabelle Cremer, Marc Pallardy, Paule Opolon, Vichnou Poirier-Colame, Guido Kroemer, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Department of Immunology, Duke University Medical Center, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), School of Medicine, Université Paris-Sud - Paris 11 (UP11), Recepteurs et Signalisation des Interleukines (U749), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pédiatrie, Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Département de biologie et pathologie médicales [Gustave Roussy], Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Università di Genova, Dipartimento di Medicina Sperimentale, Universita degli studi di Genova, Biochemistry, Ghent University [Belgium] (UGENT), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Département de pathologie, Institut Bergonié - CRLCC Bordeaux, Département de Médecine Nucléaire, Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratory of Human Genetics of Infectious Diseases, Apoptose, cancer et immunité (U848), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Recepteurs et Signalisation des Interleukines ( U749 ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Vectorologie et transfert de gènes ( VTG / UMR8121 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), University of Genova, Ghent University [Belgium] ( UGENT ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Université Claude Bernard Lyon 1 ( UCBL ), Apoptose, cancer et immunité ( U848 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Genova = University of Genoa (UniGe), Universiteit Gent = Ghent University (UGENT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Universiteit Gent = Ghent University [Belgium] (UGENT)

Subjects
MESH: Interleukin-12, MESH : Alternative Splicing, MESH: Protein Isoforms, MESH: Lysosomal-Associated Membrane Protein 1, 0302 clinical medicine, Interferon, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Receptor, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, MESH : Prognosis, MESH : Gastrointestinal Stromal Tumors, GiST, MESH : Lysosomal-Associated Membrane Protein 1, MESH: Alternative Splicing, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, General Medicine, Prognosis, Interleukin-12, MESH: Proto-Oncogene Proteins c-kit, Killer Cells, Natural, Proto-Oncogene Proteins c-kit, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH : Killer Cells, Natural, Sarcoma, MESH: Natural Cytotoxicity Triggering Receptor 3, Tyrosine kinase, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, Gene isoform, MESH : Natural Cytotoxicity Triggering Receptor 3, MESH: Cell Line, Tumor, Stromal cell, MESH: Interferon-gamma, Gastrointestinal Stromal Tumors, Biology, Polymorphism, Single Nucleotide, MESH : Proto-Oncogene Proteins c-kit, MESH: Prognosis, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Lysosomal-Associated Membrane Protein 1, Cell Line, Tumor, MESH : Interleukin-12, medicine, Humans, MESH : Interferon-gamma, 030304 developmental biology, MESH: Humans, Natural Cytotoxicity Triggering Receptor 3, MESH : Cell Line, Tumor, Tumor Necrosis Factor-alpha, MESH : Humans, MESH : Protein Isoforms, medicine.disease, Alternative Splicing, MESH: Tumor Necrosis Factor-alpha, Immunology, Cancer research, 030215 immunology
Abstract

International audience; The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.

Published
2010
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25. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients

Author

Julien Taieb, Jean-François Emile, Jean-Yves Blay, Laurence Zitvogel, Stefan Michiels, Christophe Borg, Nathalie Chaput, Céline Nonn, François Ghiringhelli, Caroline Flament, Cédric Ménard, Axel Le Cesne, Nicolas F. Delahaye, Caroline Robert, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine, Centre Léon Bérard [Lyon], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Méthodologie et épidémiologie clinique en oncologie moléculaire (U1018 (Équipe 2)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Institut Gustave Roussy (IGR), Saas, Philippe, and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, Cancer Research, MESH: Piperazines, Piperazines, 0302 clinical medicine, Stromal tumor, 10. No inequality, 0303 health sciences, MESH: Middle Aged, GiST, MESH: Dendritic Cells, Hazard ratio, Exons, Middle Aged, 3. Good health, Killer Cells, Natural, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, Benzamides, Imatinib Mesylate, MESH: NK Cell Lectin-Like Receptor Subfamily K, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Natural Cytotoxicity Triggering Receptor 3, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Gastrointestinal Stromal Tumors, MESH: Interferon-gamma, Antineoplastic Agents, Natural killer cell, Interferon-gamma, 03 medical and health sciences, Internal medicine, medicine, Humans, 030304 developmental biology, Natural Cytotoxicity Triggering Receptor 3, MESH: Humans, Proportional hazards model, business.industry, Cancer, Imatinib, MESH: Interleukin-2, Dendritic Cells, medicine.disease, MESH: Male, Pyrimidines, Imatinib mesylate, MESH: Pyrimidines, Immunology, Interleukin-2, MESH: Antineoplastic Agents, business, MESH: Exons, MESH: Female
Abstract

Clinical outcomes of gastrointestinal stromal tumor (GIST)–bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activity. We addressed whether NK cell functions could predict long term survival with IM. NK cell functions were followed up in 77 GIST patients enrolled onto two phase III trials. “Immunologic responders” were defined as patients whose NK cell IFN-γ values after 2 months of IM were higher than or equal to the baseline value at entry into the trial. The prognostic effect of IFN-γ on progression-free survival was assessed by a Wald test in a Cox regression analysis using the landmark method and stratified by trial and on the c-kit mutational status. Fifty-six patients were evaluable for the NK cell IFN-γ responses at baseline and 2 months. Their median follow-up for progression-free survival was 3.7 years. Thirty-four of 56 patients were immunologic responders to IM. In the Cox regression analysis, immunologic responders possessed a hazard ratio of progression or death equal to 0.29 (95% confidence interval, 0.12–0.70; P = 0.006) compared with nonresponders. Kaplan-Meier 2-year survival estimates were 85% for immunologic responders and 50% for nonresponders. Moreover, the immunologic response added prognostic value to the c-kit mutation. The NK cell IFN-γ production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM. [Cancer Res 2009;69(8):3563–9]

Published
2009
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26. Dendritic cells and innate defense against tumor cells

Author

Grégoire Mignot, Evelyn Ullrich, Magali Terme, Nathalie Chaput, Laurence Chaperot, Caroline Flament, Cédric Ménard, Mathieu Bonmort, Laurence Zitvogel, Joel Plumas, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 9 (Immunobiologie et Immunothérapie des Cancers), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire recherche et développement, EFS, Laboratoire recherche et développement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARC, INCA, Cancéropole, ligue nationale contre le cancer, Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chaperot, Laurence

Subjects
MESH: Interferon Type I, Endocrinology, Diabetes and Metabolism, MESH: Interleukin-15, MESH: Piperazines, Apoptosis, Piperazines, MESH: Cancer Vaccines, MESH: Uric Acid, 0302 clinical medicine, MESH: HMGB1 Protein, Neoplasms, Immunology and Allergy, MESH: Interferons, MESH: Neoplasms, HMGB1 Protein, MESH: CpG Islands, Interleukin-15, 0303 health sciences, Toll-like receptor, MESH: Cytokines, MESH: Dendritic Cells, T helper cell, T-Lymphocytes, Helper-Inducer, MESH: Granulocyte-Macrophage Colony-Stimulating Factor, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, Oligodeoxyribonucleotides, 030220 oncology & carcinogenesis, Benzamides, Interferon Type I, Imatinib Mesylate, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Killer Cells, Natural, Fas Ligand Protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Interferon Type II, T cell, Immunology, MESH: Receptor Cross-Talk, Biology, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Immune system, medicine, Biomarkers, Tumor, Humans, MESH: T-Lymphocytes, Helper-Inducer, Antigen-presenting cell, 030304 developmental biology, MESH: Immunity, Natural, Tumor microenvironment, Innate immune system, MESH: Humans, MESH: Apoptosis, Granulocyte-Macrophage Colony-Stimulating Factor, Dendritic cell, Dendritic Cells, Receptor Cross-Talk, Immunity, Innate, MESH: Fas Ligand Protein, Uric Acid, Pyrimidines, MESH: Pyrimidines, MESH: Tumor Markers, Biological, MESH: Oligodeoxyribonucleotides, CpG Islands, Interferons
Abstract

International audience; Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells.

Published
2008
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27. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner

Author

Jacky Bernard, Antônio C. Freitas, Jean-Yves Blay, Caroline Flament, Orianne Wagner-Ballon, Laurence Zitvogel, Cédric Ménard, A. Lecesne, Magali Terme, T. Tursz, Caroline Robert, Bernard Escudier, William Vainchencker, Eric Vivier, Claude Capron, Julien Taieb, Sophie Caillat-Zucman, François Ghiringhelli, Sophie Novault, Nathalie Chaput, Pierre E. Puig, François Martin, Rôle des cellules dendritiques dans la régulation des effecteurs de l'immunité antitumorale, Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hematopoïèse et Cellules Souches ( U362 ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Jean Godineau, Etablissement Français du Sang, Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Biologie des Populations Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïèse et Cellules Souches (U362), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Cytokines, MESH: Flow Cytometry, MESH : Immunity, Natural, MESH: T-Ly, Lymphocyte Activation, T-Lymphocytes, Regulatory, Mice, Interleukin 21, 0302 clinical medicine, T-Lymphocyte Subsets, Transforming Growth Factor beta, Neoplasms, MESH : Receptors, Immunologic, MESH : Cell Proliferation, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Neoplasms, IL-2 receptor, Receptors, Immunologic, 0303 health sciences, MESH: Cytokines, hemic and immune systems, Flow Cytometry, Natural killer T cell, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, Interleukin 12, Cytokines, Receptors, Natural Killer Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, France, MESH : Killer Cells, Natural, MESH : Cytotoxicity Tests, Immunologic, MESH: Killer Cells, Natural, MESH: Cell Line, Tumor, MESH : Flow Cytometry, Immunology, chemical and pharmacologic phenomena, MESH: Cytotoxicity Tests, Immunologic, MESH : Mice, Inbred C57BL, Biology, Article, Natural killer cell, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH: Cell Proliferation, MESH : Mice, medicine, Animals, Humans, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH : France, MESH: Mice, MESH: Receptors, Immunologic, MESH : Lymphocyte Activation, Cell Proliferation, 030304 developmental biology, MESH: Immunity, Natural, Lymphokine-activated killer cell, MESH: Humans, MESH : Cell Line, Tumor, MESH : Humans, Cytotoxicity Tests, Immunologic, NKG2D, MESH : T-Ly, MESH : Neoplasms, Immunity, Innate, Mice, Inbred C57BL, MESH: France, MESH : Animals, 030215 immunology
Abstract

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

Published
2007
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28. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines

Author

Julien, Taieb, Nathalie, Chaput, Noël, Schartz, Stéphan, Roux, Sophie, Novault, Cédric, Ménard, François, Ghiringhelli, Magali, Terme, Antoine F, Carpentier, Guillaume, Darrasse-Jèze, Guillaume, Darrasse-Jèse, François, Lemonnier, Laurence, Zitvogel, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Immunité Cellulaire Antivirale, Institut Pasteur [Paris], This work is supported by a Poste d’accueil Institut National de la Santé et de la Recherche Médicale and Assistance Publique Hopitaux de Paris (to J.T.) and is supported by a European fellowship in the QLRT-2001-00093 and by Association de Recherche contre le Cancer (to N.C.). This work has also been supported by the EC ALLOSTEM grant, by DC THERA European grant, by the Association de Recherche contre le Cancer, and by the LIGUE LABELLISEE française contre le Cancer cancéropôle, Ile de France., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Novault, Sophie

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Melanoma, Experimental, MESH: Vaccines, Subunit, MESH: Adjuvants, Immunologic, CD8-Positive T-Lymphocytes, Pharmacology, MESH: Antineoplastic Agents, Alkylating, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, MESH: Mice, Knockout, MESH: Cancer Vaccines, Mice, 0302 clinical medicine, MESH: Cytoplasmic Vesicles, polycyclic compounds, Immunology and Allergy, MESH: Animals, IL-2 receptor, Cells, Cultured, Mice, Knockout, Mice, Inbred BALB C, MESH: Dendritic Cells, FOXP3, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], MESH: Melanoma, Experimental, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Vaccines, Subunit, MESH: Immunotherapy, Adoptive, Female, hormones, hormone substitutes, and hormone antagonists, MESH: Cells, Cultured, MESH: Killer Cells, Natural, MESH: Mice, Transgenic, T cell, Immunology, MESH: Mice, Inbred BALB C, Mice, Transgenic, Biology, Major histocompatibility complex, Cancer Vaccines, Exosome, 03 medical and health sciences, Adjuvants, Immunologic, medicine, Animals, Humans, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Mice, MESH: Humans, MESH: T-Lymphocytes, Regulatory, Cytoplasmic Vesicles, MESH: Cyclophosphamide, Dendritic Cells, Immunotherapy, Microvesicles, CTL, biology.protein, MESH: Female, 030215 immunology
Abstract

Dendritic cell-derived exosomes (DEX) are nanomeric vesicles harboring MHC/peptide complexes capable of promoting primary T cell responses and tumor rejection in the presence of adjuvants. In this study, we show that, in the absence of adjuvants, DEX mediate potent Ag-dependent antitumor effects against preestablished tumors in mice pretreated with immunopotentiating dosing of cyclophosphamide. Cyclophosphamide could 1) abolish the suppressive function of CD4+CD25+Foxp3+ regulatory T cells, 2) markedly enhance the magnitude of secondary but not primary CTL responses induced by DEX vaccines, 3) synergize with DEX in therapy but not prophylaxis tumor models. Therefore, therapeutic vaccines such as DEX aimed at boosting tumor-primed effector T cells could benefit procedures that minimize the effects of CD4+CD25+ regulatory T cells.

Published
2006
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29. Activated CD4(+) T Cells impact adipose-serived stromal cell function through CD40-dependant activation

Author

Isabelle Bezier, Séverine Loisel, Nicolas Bertheuil, Léa Verdière, Nadège Bescher, Joelle Dulong, Cédric Ménard, Maelle Latour, David Roulois, Karin Tarte, CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), Etablissement français du sang [Rennes] (EFS Bretagne), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )

Subjects
Cancer Research, Chemokine, Stromal cell, Immunology, Adipose tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Inflammation, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Transplantation, CD40, biology, Chemistry, Mesenchymal stem cell, hemic and immune systems, Cell Biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, medicine.symptom
Abstract

Background & Aim Although native bone marrow-derived mesenchymal stromal cells (BM-MSC) have been described to express CD40, how CD40 is regulated on MSC, and whether CD40 signaling affects MSC activation and function remain unknown. We recently demonstrated that adipose-derived stromal cells (ASC) exhibit a stronger capacity to inhibit immune response than BM-MSC, supporting their use for clinical applications to treat inflammatory diseases and degenerative disorders. Moreover, obesity is associated with adipose tissue inflammation and recruitment of immune cells that could in turn affect the phenotype of native ASC in situ. We thus decided to explore CD40 regulation, signalization, and function on native and in vitro-expanded ASC. Methods, Results & Conclusion Adipose Tissue Stromal Vascular Fractions (ATSVF) were obtained from obese and non-obese donors during lipectomy. Comparison of gene expression was carried out by using RNA sequencing. Some gene expression levels were assessed by QPCR on the total cells or on the CD146− CD34+ Lin− purified ASC. Next, ASC isolated by adhesion in culture were submitted to various stimuli or co-culture with activated CD4+ T cells. Changes in gene expression and secretion profiles were studied by Q-PCR and ELISA. Neutrophil migration was measured through Transwell and involvement of the candidate pathways was assessed by using specific siRNAs. We first revealed through gene expression profiling that the inflammatory signature found in adipose tissue stromal vascular fractions from obese patients included an upregulation of CD40L and was associated with a simultaneous induction of CD40 expression on native ASC. We further confirmed that inflammatory cytokines and direct contact with activated CD4+ T cells upregulated membrane CD40 expression on in vitro-expanded ASC. Stimulation of ASC by CD40L induced a modification of their gene expression profile evaluated by RNAseq reflecting an activation of NF-kB pathway. In agreement, we confirmed by DNA-binding ELISA, the activation of NF-kB pathways by CD40L stimulation. More specifically we focused on the strong induction of inflammatory chemokines, in particular IL-8, triggered on ASC by CD4+ T cells in a CD40/CD40L-dependant manner. Accordingly, CD40L-stimulated ASC recruited more efficiently neutrophils. Overall, these data strongly suggest an interaction between CD4+ T cells, ASC, and neutrophils within inflammatory sites. This observation must be kept in mind when using ASC to treat inflammatory diseases.

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