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1. Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction.

Author

Zacchigna, Serena, Martinelli, Valentina, Moimas, Silvia, Colliva, Andrea, Anzini, Marco, Nordio, Andrea, Costa, Alessia, Rehman, Michael, Vodret, Simone, Pierro, Cristina, Colussi, Giulia, Zentilin, Lorena, Gutierrez, Maria Ines, Dirkx, Ellen, Long, Carlin, Sinagra, Gianfranco, Klatzmann, David, and Giacca, Mauro

Subjects
CHO Cells, Myocytes, Cardiac, Animals, Mice, Inbred C57BL, Cricetulus, Mice, Rats, Myocardial Infarction, Culture Media, Conditioned, Cell Proliferation, Pregnancy, Female, Cricetinae, T-Lymphocytes, Regulatory, Cell- and Tissue-Based Therapy, Culture Media, Conditioned, Inbred C57BL, Myocytes, Cardiac, T-Lymphocytes, Regulatory
Abstract

Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction.

Published
2018

2. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Author

Hannani, Dalil, Vétizou, Marie, Enot, David, Rusakiewicz, Sylvie, Chaput, Nathalie, Klatzmann, David, Desbois, Melanie, Jacquelot, Nicolas, Vimond, Nadège, Chouaib, Salem, Mateus, Christine, Allison, James P, Ribas, Antoni, Wolchok, Jedd D, Yuan, Jianda, Wong, Philip, Postow, Michael, Mackiewicz, Andrzej, Mackiewicz, Jacek, Schadendorff, Dirk, Jaeger, Dirk, Korman, Alan J, Bahjat, Keith, Maio, Michele, Calabro, Luana, Teng, Michele WL, Smyth, Mark J, Eggermont, Alexander, Robert, Caroline, Kroemer, Guido, and Zitvogel, Laurence

Subjects
Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal, CD4-Positive T-Lymphocytes, CTLA-4 Antigen, Cohort Studies, Disease Models, Animal, Female, Humans, Immunotherapy, Interleukin-2 Receptor alpha Subunit, Ipilimumab, Male, Melanoma, Mice, Mice, Inbred C57BL, Middle Aged, Receptors, Interleukin-2, Recombinant Proteins, T-Lymphocytes, Regulatory, Up-Regulation, Young Adult, ipilimumab, CTLA-4 blockade, IL-2, CD122, sCD25, tumor immunotherapy, cancer, Biochemistry and Cell Biology, Clinical Sciences, Developmental Biology
Abstract

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.

Published
2015

3. Interleukin-5–producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy

Author

Van Gool, Frédéric, Molofsky, Ari B, Morar, Malika M, Rosenzwajg, Michelle, Liang, Hong-Erh, Klatzmann, David, Locksley, Richard M, and Bluestone, Jeffrey A

Subjects
Biomedical and Clinical Sciences, Immunology, Autoimmune Disease, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Antibodies, Cell Proliferation, Eosinophilia, Humans, Immunity, Innate, Interleukin-2, Interleukin-5, Lymphocytes, Mice, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics
Abstract

Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate. Using genetic approaches in mice, we demonstrate that activation of ILC2 was responsible for the eosinophilia observed with IL-2 therapy. These observations reveal a novel cellular network that is activated during IL-2 treatment. A better understanding of the cross talk between these cell populations may lead to more effective targeting of IL-2 to treat autoimmune disease.

Published
2014

4. Enveloped virus-like particle expression of human cytomegalovirus glycoprotein B antigen induces antibodies with potent and broad neutralizing activity.

Author

Kirchmeier, Marc, Fluckiger, Anne-Catherine, Soare, Catalina, Bozic, Jasminka, Ontsouka, Barthelemy, Ahmed, Tanvir, Diress, Abebaw, Schödel, Florian, Plotkin, Stanley, Dalba, Charlotte, Klatzmann, David, Anderson, David, and Pereira, Lenore

Subjects
Animals, Antibodies, Neutralizing, Antibodies, Viral, Cytomegalovirus, Cytomegalovirus Infections, Cytomegalovirus Vaccines, Epithelial Cells, Female, Mice, Mice, Inbred BALB C, Vaccines, Virus-Like Particle, Viral Envelope Proteins
Abstract

A prophylactic vaccine to prevent the congenital transmission of human cytomegalovirus (HCMV) in newborns and to reduce life-threatening disease in immunosuppressed recipients of HCMV-infected solid organ transplants is highly desirable. Neutralizing antibodies against HCMV confer significant protection against infection, and glycoprotein B (gB) is a major target of such neutralizing antibodies. However, one shortcoming of past HCMV vaccines may have been their failure to induce high-titer persistent neutralizing antibody responses that prevent the infection of epithelial cells. We used enveloped virus-like particles (eVLPs), in which particles were produced in cells after the expression of murine leukemia virus (MLV) viral matrix protein Gag, to express either full-length CMV gB (gB eVLPs) or the full extracellular domain of CMV gB fused with the transmembrane and cytoplasmic domains from vesicular stomatitis virus (VSV)-G protein (gB-G eVLPs). gB-G-expressing eVLPs induced potent neutralizing antibodies in mice with a much greater propensity toward epithelial cell-neutralizing activity than that induced with soluble recombinant gB protein. An analysis of gB antibody binding titers and T-helper cell responses demonstrated that high neutralizing antibody titers were not simply due to enhanced immunogenicity of the gB-G eVLPs. The cells transiently transfected with gB-G but not gB plasmid formed syncytia, consistent with a prefusion gB conformation like those of infected cells and viral particles. Two of the five gB-G eVLP-induced monoclonal antibodies we examined in detail had neutralizing activities, one of which possessed particularly potent epithelial cell-neutralizing activity. These data differentiate gB-G eVLPs from gB antigens used in the past and support their use in a CMV vaccine candidate with improved neutralizing activity against epithelial cell infection.

Published
2014

6. In vivo mature immunological synapses forming SMACs mediate clearance of virally infected astrocytes from the brain

Author

Barcia, Carlos, Thomas, Clare E, Curtin, James F, King, Gwendalyn D, Wawrowsky, Kolja, Candolfi, Marianela, Xiong, Wei-Dong, Liu, Chunyan, Kroeger, Kurt, Boyer, Olivier, Kupiec-Weglinski, Jerzy, Klatzmann, David, Castro, Maria G, and Lowenstein, Pedro R

Subjects
Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Adenoviridae, Animals, Astrocytes, Brain, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Communication, Genes, Viral, Immune System, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Male, Mice, Multiprotein Complexes, Phosphorylation, Rats, Rats, Sprague-Dawley, ZAP-70 Protein-Tyrosine Kinase, Medical and Health Sciences, Immunology
Abstract

The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell-antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer-target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor-rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in vivo has cast doubts on its functional relevance. Herein, we demonstrate that the in vivo formation of SMAC at immunological synapses between effector CD8 + T cells and target cells precedes and mediates clearance of virally infected brain astrocytes. JEM © The Rockefeller University Press.

Published
2006

9. Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice.

Author

Mhanna, Vanessa, Fourcade, Gwladys, Barennes, Pierre, Quiniou, Valentin, Pham, Hang P., Ritvo, Paul-Gydeon, Brimaud, Faustine, Gouritin, Bruno, Churlaud, Guillaume, Six, Adrien, Mariotti-Ferrandiz, Encarnita, and Klatzmann, David

Subjects
REGULATORY T cells, CLONE cells, T cells, MICE, LABORATORY mice, RESEARCH, INTERLEUKIN-2, ANIMAL experimentation, RESEARCH methodology, CELL receptors, TYPE 1 diabetes, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies
Abstract

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic β-cells by autoreactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated the contribution to diabetes of the T-cell receptor (TCR) repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. Interleukin-2 (IL-2) administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2-expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2. [ABSTRACT FROM AUTHOR]

Published
2021
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10. High diversity of the immune repertoire in humanized NOD.SCID.gamma c-/- mice

Author

Marodon, Gilles, Desjardins, Delphine, Mercey, Laetitia, Baillou, Claude, Parent, Pierric, Manuel, Manuarii, Caux, Christophe, Bellier, Bertrand, Pasqual, Nicolas, Klatzmann, David, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), 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 Pierre et Marie Curie - Paris 6 (UPMC), Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Unité d'hémato-oncologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Systématique, adaptation, évolution (SAE), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de biothérapies [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), 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 Pierre et Marie Curie - Paris 6 ( UPMC ), Biologie et thérapeutique des pathologies immunitaires ( BTPI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Systématique, adaptation, évolution ( SAE ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, MESH: Mice, Inbred NOD, MESH : Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, MESH : Immunoglobulin Heavy Chains, MESH: Flow Cytometry, Hepacivirus, Mice, SCID, Polymerase Chain Reaction, MESH: Mice, Knockout, MESH : Hepacivirus, MESH: Animals, Newborn, Mice, Mice, Inbred NOD, MESH : Antigens, CD45, MESH : Female, MESH: Animals, MESH: Hepacivirus, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, MESH: Mice, SCID, MESH : Polymerase Chain Reaction, Mice, Knockout, Immunity, Cellular, MESH: Receptors, Antigen, T-Cell, alpha-beta, MESH : Animals, Newborn, Receptors, Antigen, T-Cell, gamma-delta, Flow Cytometry, MESH : Receptors, Antigen, T-Cell, gamma-delta, MESH : Receptors, Antigen, T-Cell, alpha-beta, MESH : Immunophenotyping, MESH: Immunization, Female, Immunoglobulin Heavy Chains, MESH: Immunoglobulin Heavy Chains, MESH: Immunophenotyping, MESH : Flow Cytometry, MESH : Male, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, MESH: Antigens, CD45, Immunophenotyping, MESH: Immunity, Cellular, MESH: Receptors, Antigen, T-Cell, gamma-delta, MESH : Mice, Animals, Humans, MESH: Mice, MESH : T-Lymphocytes, MESH: Humans, MESH : Mice, Inbred NOD, MESH : Humans, MESH: Clone Cells, MESH : Clone Cells, MESH : Immunity, Cellular, MESH: Polymerase Chain Reaction, MESH : Immunization, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, MESH : Mice, SCID, MESH: Male, Clone Cells, MESH: T-Lymphocytes, Animals, Newborn, MESH : Mice, Knockout, Leukocyte Common Antigens, Immunization, MESH : Animals, MESH: Female, MESH: Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
Abstract

International audience; The diversity of the human immune repertoire and how it relates to a functional immune response has not yet been studied in detail in humanized NOD.SCID.gammac(-/-) immunodeficient mice. Here, we used a multiplex PCR on genomic DNA to quantify the combinatorial diversity of all possible V-J rearrangements at the TCR-beta chain and heavy chain Ig locus. We first show that the combinatorial diversity of the TCR-beta chain generated in the thymus was well preserved in the periphery, suggesting that human T cells were not vastly activated in mice, in agreement with phenotypic studies. We then show that the combinatorial diversity in NOD.SCID.gammac(-/-) mice reached 100% of human reference samples for both the TCR and the heavy chain of Ig. To document the functionality of this repertoire, we show that a detectable but weak HLA-restricted cellular immune response could be elicited in reconstituted mice after immunization with an adenoviral vector expressing HCV envelope glycoproteins. Altogether, our results suggest that humanized mice express a diversified repertoire and are able to mount antigen-specific immune responses.

Published
2009
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11. In situ transduction of stromal cells and thymocytes upon intrathymic injection of lentiviral vectors

Author

Klatzmann David and Marodon Gilles

Subjects
lcsh:Immunologic diseases. Allergy, Recombinant Fusion Proteins, T-Lymphocytes, Genetic Vectors, Green Fluorescent Proteins, Receptors, Antigen, T-Cell, Clonal Deletion, Hemagglutinin Glycoproteins, Influenza Virus, Mice, Transgenic, T-Cell Antigen Receptor Specificity, Thymus Gland, Injections, Mice, Genes, Reporter, Transduction, Genetic, Genes, Synthetic, Immune Tolerance, Animals, Transgenes, Promoter Regions, Genetic, Methodology Article, Lentivirus, Mice, Inbred C57BL, Phosphoglycerate Kinase, Stromal Cells, lcsh:RC581-607
Abstract

Background The thymus is the primary site for T-cell development and induction of self-tolerance. Previous approaches towards manipulation of T-cell differentiation have used intrathymic injection of antigens, as proteins, cells or adenoviruses, leading to transient expression of the foreign protein. Lentiviral vectors, due to their unique ability to integrate into the genome of quiescent cells, may be best suited for long-term expression of a transgene in the thymus. Results Young adult mice were injected in the thymus with lentiviral vectors expressing eGFP or the hemaglutinin of the Influenza virus under the control of the ubiquitous phospho glycerate kinase promoter. Thymi were examined 5 to 90 days thereafter directly under a UV-light microscope and by flow cytometry. Intrathymic injection of lentiviral vectors predominantly results in infection of stromal cells that could be detected for at least 3 months. Importantly, hemaglutinin expression by thymic stromal cells mediated negative selection of thymocytes expressing the cognate T-cell receptor. In addition and despite the low multiplicity of infection, transduced thymocytes were also detected, even 30 days after injection. Conclusions Our results demonstrate that intrathymic delivery of a lentiviral vector is an efficient means for stable expression of a foreign gene in the thymus. This new method of gene delivery may prove useful for induction of tolerance to a specific antigen and for gene therapy of severe combined immunodeficiencies.

Published
2004

12. Reply: Beneficial effect of interleukin-2-based immunomodulation in Alzheimer-like pathology.

Author

Alves, Sandro, Churlaud, Guillaume, Klatzmann, David, and Cartier, Nathalie

Subjects
INTERLEUKIN-2, ALZHEIMER'S disease treatment, ALZHEIMER'S disease prevention, THERAPEUTICS, IMMUNE system physiology, ALZHEIMER'S disease, AMYLOIDOSIS, ANIMAL experimentation, COMPARATIVE studies, RESEARCH methodology, MEDICAL cooperation, MEMORY, MICE, RESEARCH, EVALUATION research
Published
2017
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13. Suicide Gene-Mediated Modulation of Graft-Versus-Host Disease.

Author

Cohen, José L., Boyer, Olivier, Thomas-Vaslin, Véronique, and Klatzmann, David

Subjects
GRAFT versus host disease, BONE marrow transplant complications, LEUKEMIA, LYMPHOMAS, GRAFT versus host reaction, IMMUNOLOGIC diseases
Abstract

The development of suicide genes and progress in retroviral gene transfer to T ccHs open new perspectives for the treatment of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) for leukemia and lymphoma. Indeed, suicide genes that metabolize inactive prodrugs into compounds toxic for dividing cells provide a powerful means for the pharmacogenetic control of T-cell reactivity. Here, we demonstrate the selective destruction of activated TK-transgenic T-cells in vivo and develop two new transgenic lines which should be useful for preclinical studies of suicide gene therapy strategies for GVHD. [ABSTRACT FROM AUTHOR]

Published
1999
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14. Retrovirus-Based Virus-Like Particle Immunogenicity and Its Modulation by Toll-Like Receptor Activation.

Author

Pitoiset, Fabien, Vazquez, Thomas, Levacher, Beatrice, Nehar-Belaid, Djamel, Dérian, Nicolas, Vigneron, James, Klatzmann, David, and Bellier, Bertrand

Subjects
*VIRUS-like particles, *IMMUNOGENETICS, *IMMUNE response, *RETROVIRUS genetics, *TOLL-like receptors
Abstract

Retrovirus-derived virus-like particles (VLPs) are particularly interesting vaccine platforms, as they trigger efficient humoral and cellular immune responses and can be used to display heterologous antigens. In this study, we characterized the intrinsic immunogenicity of VLPs and investigated their possible adjuvantization by incorporation of Toll-like receptor (TLR) ligands. We designed a noncoding single-stranded RNA (ncRNA) that could be encapsidated by VLPs and induce TLR7/8 signaling. We found that VLPs efficiently induce in vitro dendritic cell activation, which can be improved by ncRNA encapsidation (ncRNAVLPs). Transcriptome studies of dendritic cells harvested from the spleens of immunized mice identified antigen presentation and immune activation as the main gene expression signatures induced by VLPs, while TLR signaling and Th1 signatures characterize ncRNAVLPs. In vivo and compared with standard VLPs, ncRNAVLPs promoted Th1 responses and improved CD8+ T cell proliferation in a MyD88-dependent manner. In an HIV vaccine mouse model, HIV-pseudotyped ncRNAVLPs elicited stronger antigen-specific cellular and humoral responses than VLPs. Altogether, our findings provide molecular evidence for a strong vaccine potential of retrovirus-derived VLPs that can be further improved by harnessing TLR-mediated immune activation. [ABSTRACT FROM AUTHOR]

Published
2017
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15. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.

Author

Dragin, Nadine, Bismuth, Jacky, Cizeron-Clairac, Géraldine, Biferi, Maria Grazia, Berthault, Claire, Serraf, Alain, Nottin, Rémi, Klatzmann, David, Cumano, Ana, Barkats, Martine, Le Panse, Rozen, and Berrih-Aknin, Sonia

Subjects
*ANTI-estrogenic diet, *ESTROGEN replacement therapy, *DIMORPHISM (Biology), *MESSENGER RNA, *PROTEIN analysis, *PROTEIN metabolism, *ANIMALS, *AUTOIMMUNE diseases, *CELL culture, *DNA, *ESTROGEN, *GENES, *HUMAN reproduction, *MICE, *PROTEINS, *THYMUS, *TRANSCRIPTION factors, *DNA methylation
Abstract

Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases. [ABSTRACT FROM AUTHOR]

Published
2016
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16. Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice

Author

Fábio B. Canto, Paula A. Borges, Tristan Courau, Claudia F. Benjamim, Ingrid Waclawiak, David Klatzmann, Janaína L. Georgii, Steven L. Kunkel, Claudio Canetti, Cyntia Pecli, Janaína F. Barros, Erivan Schnaider Ramos-Junior, Carmen Penido, Universidade Federal do Rio de Janeiro (UFRJ), Université Pierre et Marie Curie - Paris 6 (UPMC), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Michigan [Ann Arbor], University of Michigan System, Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), and KLATZMANN, DAVID

Subjects
regulatory T cell, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biochemistry, Chemokine receptor, Mice, Alloxan, DM, CCL17, Mice, Knockout, education.field_of_study, integumentary system, WT, Biopsy, Needle, Immunohistochemistry, Treg, [SDV] Life Sciences [q-bio], Cytokine, medicine.anatomical_structure, diabetes mellitus, draining lymph node, wild type, Chemokines, Receptors, CCR4, Regulatory T cell, Population, RT-PCR, Dermatology, Real-Time Polymerase Chain Reaction, reverse transcriptase PCR, Diabetes Mellitus, Experimental, Diabetes mellitus, medicine, Animals, Humans, dLN, education, Molecular Biology, Chemokine CCL22, Analysis of Variance, Wound Healing, business.industry, Cell Biology, medicine.disease, Mice, Inbred C57BL, Diabetes Mellitus, Type 1, Immunology, Chemokine CCL17, business, Wound healing, CCL22
Abstract

International audience; Wound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long-term complications associated with diabetes mellitus. The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell recruitment and activation in inflamed skin; however, the role of regulatory T cells in wounds is still not clear. Our aim was to investigate the role of CCR4 and regulatory T cells in cutaneous wound healing in diabetic mice. Alloxan-induced diabetic wild-type mice (diabetic) developed wounds that were difficult to heal, differently from CCR4 e/e diabetic mice (CCR4 e/e diabetic), and also from anti-CCL17/22 or anti-CD25einjected diabetic mice that presented with accelerated wound healing and fewer regulatory T cells in the wound bed. Consequently, CCR4 e/e diabetic mice also presented with alteration on T cells population in the wound and draining lymph nodes; on day 14, these mice also displayed an increase of collagen fiber deposition. Still, cytokine levels were decreased in the wounds of CCR4 e/e diabetic mice on day 2. Our data suggest that the receptor CCR4 and regulatory T cells negatively affect wound healing in diabetic mice.

Published
2019
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17. Regulatory T Cells Orchestrate Similar Immune Evasion of Fetuses and Tumors in Mice

Author

David Klatzmann, Nicolas Derian, Djamel Nehar-Belaid, Maria Grazia Ruocco, Tristan Courau, Laura Florez, Immunologie - Immunopathologie - Immunothérapeutique (I3), 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), Immunologie - Immunopathologie - Immunothérapie (I3), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), KLATZMANN, DAVID, Service de biothérapies [CHU Pitié-Salpétrière], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Regulatory T cell, [SDV]Life Sciences [q-bio], animal diseases, T cell, Immunology, chemical and pharmacologic phenomena, Biology, T-Lymphocytes, Regulatory, Immune tolerance, Fetal Development, Mice, 03 medical and health sciences, Fetus, Immune system, Downregulation and upregulation, Neoplasms, Immune Tolerance, medicine, Animals, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, Tumor microenvironment, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cell growth, biochemical phenomena, metabolism, and nutrition, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Tumor Escape, bacteria, Female, Transcriptome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Embryos and tumors are both masses of dividing cells expressing foreign Ags, but they are not rejected by the immune system. We hypothesized that similar tolerogenic mechanisms prevent their rejection. Global comparison of fetal and tumor microenvironments through transcriptomics in mice revealed strikingly similar and dramatic decreases in expression of numerous immune-related pathways, including Ag presentation and T cell signaling. Unsupervised analyses highlighted the parallel kinetics and similarities of immune signature downregulation, from the very first days after tumor or embryo implantation. Besides upregulated signatures related to cell proliferation, the only significant signatures shared by the two conditions across all biological processes and all time points studied were downmodulated immune response signatures. Regulatory T cell depletion completely reverses this immune downmodulation to an immune upregulation that leads to fetal or tumor immune rejection. We propose that evolutionarily selected mechanisms that protect mammalian fetuses from immune attack are hijacked to license tumor development.

Published
2016
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18. Reply: Beneficial effect of interleukin-2-based immunomodulation in Alzheimer-like pathology

Author

David Klatzmann, Sandro Alves, Nathalie Cartier, Guillaume Churlaud, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), KLATZMANN, DAVID, Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biothérapies [CHU Pitié-Salpétrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Interleukin 2, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Amyloidosis, 3. Good health, Immunomodulation, Mice, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Alzheimer Disease, Memory, Immunology, Animals, Interleukin-2, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

International audience; No abstract available

Published
2017
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19. Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Author

Faustine Brimaud, Fabien Pitoiset, Thomas Vazquez, David Klatzmann, Guillaume Churlaud, Bertrand Bellier, James Vigneron, Benjamin Bonnet, Béatrice Levacher, Immunologie - Immunopathologie - Immunothérapeutique (I3), 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), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Immunologie - Immunopathologie - Immunothérapie (I3), Service de biothérapies [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], KLATZMANN, DAVID, Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
0301 basic medicine, Allergy, Arachis, Regulatory T cell, Ovalbumin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Food allergy, medicine, Immunology and Allergy, Animals, Humans, Mast Cells, Th1-Th2 Balance, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Immunosuppression, Allergens, medicine.disease, Mast cell, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Self Tolerance, Interleukin-2, Female, Immunotherapy, business, Food Hypersensitivity, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

Regulatory T cells (Tregs) are pivotal for maintenance of immune self-tolerance and also regulate immune responses to exogenous Ags, including allergens. Both decreased Treg number and function have been reported in allergic patients, offering new therapeutic perspectives. We previously demonstrated that Tregs can be selectively expanded and activated by low doses of IL-2 (ld-IL-2) inducing immunoregulation without immunosuppression and established its protective effect in autoimmune diseases. In this study, we evaluated the ability of ld-IL-2 to control allergy in an experimental model of food allergy. Ld-IL-2 induced Treg expansion and activation that elicited protection against clinical manifestations of food allergy in two mouse models with OVA and peanut. This clinical effect was lost in Treg-depleted mice, demonstrating the major contribution of Tregs in ld-IL-2 efficacy. Mechanistic studies further indicated that protection from allergy could be explained by a Treg-dependent local modification of the Th1/Th2 balance and an inhibition of mast cell recruitment and activation. Preventive and therapeutic effects of ld-IL-2 were observed over a 7-mo-period, highlighting its long-term efficacy. This study demonstrated that ld-IL-2 is efficient to prevent and to treat allergic immune responses, and thus represents a promising therapeutic strategy for managing allergic diseases.

Published
2016
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20. TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

Author

Tristan Courau, Faustine Brimaud, Bertrand Bellier, Djamel Nehar-Belaid, Thomas Vazquez, Béatrice Levacher, David Klatzmann, Laura Florez, Immunologie - Immunopathologie - Immunothérapie (I3), 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), Immunologie - Immunopathologie - Immunothérapeutique (I3), Service de biothérapies [CHU Pitié-Salpétrière], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), KLATZMANN, DAVID, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and CHU Pitié-Salpêtrière [AP-HP]

Subjects
0301 basic medicine, Vascular Endothelial Growth Factor A, T cell, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cell, Biology, T-Lymphocytes, Regulatory, Immune tolerance, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Downregulation and upregulation, Transforming Growth Factor beta, Cell Line, Tumor, Neoplasms, medicine, Immune Tolerance, Gene silencing, Animals, Gene Silencing, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Medicine, Immunotherapy, Transforming growth factor beta, 3. Good health, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Cancer research, biology.protein, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-β pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-β in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-β resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-β and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-β silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti-PD-1/anti-CTLA-4 treatment. Thus, TGF-β and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.

Published
2016
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