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1. Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines

Author

Morgan Grau, Madiha Derouazi, and Paul R. Walker

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, medicine.medical_treatment, Review, Cell-Penetrating Peptides, Cancer vaccines, CD8-Positive T-Lymphocytes, Tumor antigens, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Immune system, Antigen, Antigens, Neoplasm, Neoplasms, medicine, Humans, Molecular Biology, Pharmacology, ddc:616, Cell penetrating peptides, Antigen processing, business.industry, Cancer, Cell Biology, Immunotherapy, medicine.disease, Vaccination, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Cell-penetrating peptide, Molecular Medicine, business
Abstract

Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient's immune system against tumor-derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies.

Published
2018

2. MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype

Author

Elsa Kress, Mathias Heikenwalder, Gerard Lina, David Bauché, Saskia Lippens, Claire Macari, Marie-Cécile Michallet, Mathias Chamaillard, Sophia Djebali, Emilie Plantamura, Lyvia Moudombi, Jacqueline Marvel, Christophe Caux, Julien C. Marie, Annabelle Cesaro, Lilia Boucinha, Amiran Dzutsev, Jean-Philippe Rasigade, Ulrike Rothermel, Giorgio Trinchieri, Azzak Bentaher-Belaaouaj, Oana Dumitrescu, Morgan Grau, Michelina Plateroti, Clovis Bondu, Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer Inflammation Program [Frederick], Center for Cancer Research, Leidos Biomedical Research, Inc [Frederick, MD, USA], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), 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), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hospices Civils de Lyon (HCL), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], We acknowledge the contributions of the Structure Fédérative de Recherche BioSciences Gerland-Lyon Sud (UMS3444/US8-Ecole Normale Superieure de Lyon, Universite Claude Bernard de Lyon CNRS, INSERM) facilities, especially AniRA ImmOS. This work was supported by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Lyon I, Hospices Civils de Lyon, Association 'ARCHE,' and Agence Nationale de la Recherche Grant ANR-11-RPIB-0019-03 (to J.M.), a grant from the Département du Rhône-Fonds Européen de Développement Régional (PLATINE) (J.M.), and European Commission Grant LSHG-CT-2006-037188, The European Mouse Disease Clinic (to J.M.)., We thank J. Tschopp’s laboratory for Cardif (MAVS-deficient) mice, Martine Tomkowiak, Julien Mafille, and Barbara Gilbert for expert technical assistance, Anca Hennino for confocal images, Christophe Arpin and Mohamad Sobh for statistical data analysis, Bertrand Dubois, Marc Vocanson, and Jean-François Nicolas for helpful discussions on the DTH model, Thierry Walzer, Laurent Genestier, Bertrand Dubois, and Gérard Eberl for critical reading of the manuscript, Bariza Blanquier for help with qPCR analysis (genetic analysis), Thibault Andrieu and Sébastien Dussurgey (AniRA-Cytometry), Olga Azocar and Christophe Chamot from the Plateau Technique Imagerie/Microcopie, and the staff of AniRA-PBES, especially Jean-Louis Thoumas and Céline Angleraux., Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MICHALLET, MARIE-CECILE

Subjects
0301 basic medicine, MESH: Signal Transduction, RIG-like receptors, MESH: Intestines/immunology, MESH: Skin Diseases, Bacterial/pathology, Gut flora, MESH: Skin Diseases, Bacterial/metabolism, MESH: Mice, Knockout, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, 0302 clinical medicine, MESH: Animals, MESH: Hypersensitivity/metabolism, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Sensitization, Mice, Knockout, Multidisciplinary, integumentary system, dysbiosis, Biological Sciences, MAVS, Phenotype, 3. Good health, Intestines, medicine.anatomical_structure, MESH: Intestines/pathology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Signal Transduction, MESH: Intestines/microbiology, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Dysbiosis/complications, Biology, MESH: Gastrointestinal Microbiome/immunology, MESH: Phenotype, digestive system, 03 medical and health sciences, MESH: Skin Diseases, Bacterial/etiology, MESH: Hypersensitivity/etiology, Immunity, MESH: Mice, Inbred C57BL, MESH: Homeodomain Proteins/metabolism, medicine, Hypersensitivity, allergic skin pathologies, MESH: Hypersensitivity/pathology, Animals, Colitis, Allergic contact dermatitis, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Mice, Adaptor Proteins, Signal Transducing, Homeodomain Proteins, MESH: Adaptor Proteins, Signal Transducing/physiology, Intestinal permeability, Skin Diseases, Bacterial, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Immunology, MESH: Homeodomain Proteins/genetics, MESH: Disease Models, Animal, Dysbiosis, MESH: Female
Abstract

International audience; Prominent changes in the gut microbiota (referred to as "dysbiosis") play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I-like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of Mavs -/- mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I-like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies.

Published
2018

3. Antigen-Induced but Not Innate Memory CD8 T Cells Express NKG2D and Are Recruited to the Lung Parenchyma upon Viral Infection

Author

Thierry Walzer, Daphné Laubreton, Laurent Buffat, Anne-Laure Mathieu, Yann Leverrier, Simon de Bernard, Severine Valsesia, Erwan Ventre, Pierre-Emmanuel Jouve, Morgan Grau, Julien Mafille, Sophia Djebali, Jacqueline Marvel, Martine Tomkowiak, Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, AltraBio [Lyon], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Transgene, Immunology, Integrin, Mice, Transgenic, CD8-Positive T-Lymphocytes, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigen, Parenchyma, Gene expression, Immunology and Allergy, Cytotoxic T cell, Animals, Antigens, Lung, Inflammation, biology, NKG2D, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, NK Cell Lectin-Like Receptor Subfamily K, Virus Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Cytokine secretion, Immunologic Memory, 030215 immunology
Abstract

The pool of memory-phenotype CD8 T cells is composed of Ag-induced (AI) and cytokine-induced innate (IN) cells. IN cells have been described as having properties similar to those of AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished in mice from naturally generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared with naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins.

Published
2017

4. Antigen-induced but not innate memory CD8 T cells express NKG2D and are recruited to the lung parenchyma upon viral infection

Author

Severine Valsesia, Simon de Bernard, Anne-Laure Mathieu, Thierry Walzer, Sophia Djebali, Daphné Laubreton, Laurent Buffat, Morgan Grau, Martine Tomkowiak, Pierre-Emmanuel Jouve, Yann Leverrier, Julien Mafille, and Jacqueline Marvel

Subjects
Antigen, Gene expression, Integrin, Parenchyma, biology.protein, Cytotoxic T cell, Cytokine secretion, Biology, NKG2D, Cell biology, CD49a
Abstract

The pool of memory-phenotype CD8 T cells is composed of antigen-induced (AI) and cytokine-induced innate (IN) cells. IN have been described as having similar properties to AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished from naturally-generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared to naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins.

Published
2017

5. Immune signatures of protective spleen memory CD8 T cells

Author

Lilia Brinza, Sophia Djebali, Martine Tomkowiak, Julien Mafille, Céline Loiseau, Pierre-Emmanuel Jouve, Simon de Bernard, Laurent Buffat, Bruno Lina, Michèle Ottmann, Manuel Rosa-Calatrava, Stéphane Schicklin, Nathalie Bonnefoy, Grégoire Lauvau, Morgan Grau, Mélanie Wencker, Christophe Arpin, Thierry Walzer, Yann Leverrier, Jacqueline Marvel, Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AltraBio [Lyon], Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Albert Einstein College of Medicine [New York], Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), and Davoine, Laure-Hélène

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Mice, Transgenic, CD8-Positive T-Lymphocytes, Inbred C57BL, Transgenic, Article, Mice, Species Specificity, Animals, Homeostasis, Humans, Lung, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Principal Component Analysis, Gene Expression Profiling, Orthomyxoviridae, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mice, Inbred C57BL, Phenotype, Gene Expression Regulation, Multigene Family, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Chemokines, Peptides, Immunologic Memory, Spleen
Abstract

International audience; Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy.

Published
2016

6. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway

Author

Nicholas D. Huntington, Jessica Rabilloud, Amélien Sanlaville, Sophie Degouve, Jacqueline Marvel, Sébastien Viel, Fernando Souza Fonseca Guimaraes, Sophia Djebali, Antoine Marçais, Morgan Grau, Mark J. Smyth, Thierry Walzer, Emily Charrier, Jacques Bienvenu, Róisín M. Loftus, Liam Town, David K. Finlay, Christophe Caux, Laurent Bartholin, Julien C. Marie, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France, parent, QIMR Berghofer Medical Research Institute, School of Medicine, The University of Queensland, Trinity Biomedical Sciences Institute [Dublin], Trinity College Dublin, Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Melbourne, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cells, Autoimmunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Growth, Lymphocyte Activation, Biochemistry, immunology, 03 medical and health sciences, Interleukin 21, Mice, 0302 clinical medicine, Transforming Growth Factor beta, Germany, Serine, Animals, Humans, Homeostasis, Lymphocytes, Molecular Biology, PI3K/AKT/mTOR pathway, Interleukin-15, Mice, Knockout, Inflammation, Immunity, Cellular, Lymphokine-activated killer cell, biology, TOR Serine-Threonine Kinases, Janus kinase 3, RPTOR, Neoplasms, Experimental, Cell Biology, Transforming growth factor beta, 3. Good health, Cell biology, virology, Killer Cells, Natural, 030104 developmental biology, Interleukin 15, 030220 oncology & carcinogenesis, Immunology, biology.protein, Interleukin 12, Medicine, Cytokines, France, Infection, Laboratories, Signal Transduction
Abstract

International audience; Transforming growth factor-beta (TGF-beta) is a major immunosuppressive cytokine that maintains immune homeostasis and prevents autoimmunity through its antiproliferative and anti-inflammatory properties in various immune cell types. We provide genetic, pharmacologic, and biochemical evidence that a critical target of TGF-beta signaling in mouse and human natural killer (NK) cells is the serine and threonine kinase mTOR (mammalian target of rapamycin). Treatment of mouse or human NK cells with TGF-beta in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-beta and the mTOR inhibitor rapamycin both reduced the metabolic activity and proliferation of NK cells and reduced the abundances of various NK cell receptors and the cytotoxic activity of NK cells. In vivo, constitutive TGF-beta signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-beta receptor subunit TGF-betaRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-beta signaling in NK cells did not affect either NK cell development or homeostasis; however, it enhanced the ability of NK cells to limit metastases in two different tumor models in mice. Together, these results suggest that the kinase mTOR is a crucial signaling integrator of pro- and anti-inflammatory cytokines in NK cells. Moreover, we propose that boosting the metabolic activity of antitumor lymphocytes could be an effective strategy to promote immune-mediated tumor suppression

Published
2016

7. Regulation of Mouse NK Cell Development and Function by Cytokines

Author

Jacqueline Marvel, Thierry Walzer, Sébastien Viel, Morgan Grau, Thomas Henry, Antoine Marçais, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cytotoxicity, Immunologic, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, Cytotoxicity, [SDV]Life Sciences [q-bio], Immunology, Review Article, Biology, Signal transduction, 03 medical and health sciences, 0302 clinical medicine, Immune system, TGF beta signaling pathway, medicine, Immunology and Allergy, TGF-beta, 030304 developmental biology, Interleukin-15, 0303 health sciences, Interleukin-18, Interleukin, Interleukin-12, 3. Good health, Cytokine, Interleukin 15, Interleukin 12, Cytokines, Natural killer cells, Interferons, lcsh:RC581-607, 030215 immunology, Transforming growth factor
Abstract

International audience; Natural Killer (NK) cells are innate lymphocytes with an important role in the early defense against intracellular pathogens and against tumors. Like other immune cells, almost every aspects of their biology are regulated by cytokines. Interleukin (IL)-15 is pivotal for their development, homeostasis, and activation. Moreover, numerous other activating or inhibitory cytokines such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-18, IL-21, Transforming growth factor-β (TGFβ) and type I interferons regulate their activation and their effector functions at different stages of the immune response. In this review we summarize the current understanding on the effect of these different cytokines on NK cell development, homeostasis, and functions during steady-state or upon infection by different pathogens. We try to delineate the cellular sources of these cytokines, the intracellular pathways they trigger and the transcription factors they regulate. We describe the known synergies or antagonisms between different cytokines and highlight outstanding questions in this field of investigation. Finally, we discuss how a better knowledge of cytokine action on NK cells could help improve strategies to manipulate NK cells in different clinical situations.

Published
2013

8. c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1

Author

Benjamin Barré, Wilfried Gouraud, Loïc Campion, Morgan Grau, Philippe Juin, Sophie Barillé-Nion, Frédérique Braun, Olivier Coqueret, Catherine Charbonnel, Mario Campone, Cécile Couriaud, Fabien Gautier, Pascal Jézéquel, Yannis Guillemin, Belinda Noël, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Biogenouest Institut de Recherche Thérapeutique de l'Université de Nantes, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, Hôpital Guillaume-et-René-Laennec [Saint-Herblain], and CRLCC Paul Papin

Subjects
Cancer Research, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Gene Expression, Apoptosis, 0302 clinical medicine, RNA interference, hemic and lymphatic diseases, Gene expression, Proto-Oncogene Proteins c-myc, Promoter Regions, Genetic, Cell Aggregation, 0303 health sciences, Bcl-2-Like Protein 11, TOR Serine-Threonine Kinases, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell aggregation, Proto-Oncogene Proteins c-bcl-2, Oncology, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Molecular Medicine, Female, RNA Interference, Signal transduction, Signal Transduction, medicine.drug, Cell Survival, bcl-X Protein, Breast Neoplasms, Mechanistic Target of Rapamycin Complex 1, Biology, lcsh:RC254-282, 03 medical and health sciences, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Humans, Everolimus, neoplasms, 030304 developmental biology, Sirolimus, Research, Membrane Proteins, Proteins, Multiprotein Complexes, Cancer cell, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Apoptosis Regulatory Proteins
Abstract

Background Anti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells. Methods We used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data. Results We show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors. Conclusions This work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.

Published
2011

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