23 results on '"Roulois D"'
Search Results
2. Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells
- Author
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Roulois, D., primary, Vignard, V., additional, Gueugnon, F., additional, Labarriere, N., additional, Gregoire, M., additional, and Fonteneau, J.-F., additional
- Published
- 2011
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3. CCL2, galectin-3, and SMRP combination improves the diagnosis of mesothelioma in pleural effusions.
- Author
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Blanquart C, Gueugnon F, Nguyen JM, Roulois D, Cellerin L, Sagan C, Perigaud C, Scherpereel A, and Gregoire M
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- 2012
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4. Lymphoid-like extracellular matrix partially polarizes stroma cells toward a lymphoid phenotype
- Author
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Verdiere, L., Roulois, D., Sibut, V., Mourcin, F., Karin Tarte, 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 ), 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
[SDV.CAN]Life Sciences [q-bio]/Cancer ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
5. Core enhancers of the 3'RR optimize IgH nuclear position and loop conformation for successful oriented class switch recombination.
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Bruzeau C, Martin O, Pollet J, Thomas M, Ba Z, Roulois D, Pinaud E, and Le Noir S
- Abstract
In B lymphocytes, class switch recombination (CSR) is an essential process that adapts immunoglobulin (Ig) subtypes to antigen response. Taking place within the Ig heavy chain (IgH) locus, CSR needs controlled transcription of targeted regions governed by the IgH 3' regulatory region (3'RR). This super-enhancer is composed of four core enhancers surrounded by inverted repeated sequences, forming a quasi-palindrome. In addition to transcription, nuclear organization appears to be an important level in CSR regulation. While it is now established that chromatin loop extrusion takes place within IgH locus to facilitate CSR by bringing the donor and acceptor switch regions closer together, the underlying mechanism that triggers CSR loop formation remains partially understood. Here, by combining DNA 3D fluorescence in situhybridization with various high-throughput approaches, we deciphered critical functions for the 3'RR core enhancer element in nuclear addressing, accessibility and chromatin looping of the IgH locus. We conclude that the 3'RR core enhancers are necessary and sufficient to pre-organize the position and conformation of IgH loci in resting B-cell nuclei to enable the deletional recombination events required for productive successful CSR in activated B-cell nuclei., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2024
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6. KDM6B drives epigenetic reprogramming associated with lymphoid stromal cell early commitment and immune properties.
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Sylvestre M, Barbier N, Sibut V, Nayar S, Monvoisin C, Leonard S, Saint-Vanne J, Martin A, Guirriec M, Latour M, Jouan F, Baulande S, Bohec M, Verdière L, Mechta-Grigoriou F, Mourcin F, Bertheuil N, Barone F, Tarte K, and Roulois D
- Subjects
- Animals, Humans, Mice, Cell Differentiation genetics, Inflammation, Jumonji Domain-Containing Histone Demethylases genetics, Up-Regulation, Epigenesis, Genetic, Stromal Cells
- Abstract
Mature lymphoid stromal cells (LSCs) are key organizers of immune responses within secondary lymphoid organs. Similarly, inflammation-driven tertiary lymphoid structures depend on immunofibroblasts producing lymphoid cytokines and chemokines. Recent studies have explored the origin and heterogeneity of LSC/immunofibroblasts, yet the molecular and epigenetic mechanisms involved in their commitment are still unknown. This study explored the transcriptomic and epigenetic reprogramming underlying LSC/immunofibroblast commitment. We identified the induction of lysine demethylase 6B (KDM6B) as the primary epigenetic driver of early immunofibroblast differentiation. In addition, we observed an enrichment for KDM6B gene signature in murine inflammatory fibroblasts and pathogenic stroma of patients with autoimmune diseases. Last, KDM6B was required for the acquisition of LSC/immunofibroblast functional properties, including the up-regulation of CCL2 and the resulting recruitment of monocytes. Overall, our results reveal epigenetic mechanisms that participate in the early commitment and immune properties of immunofibroblasts and support the use of epigenetic modifiers as fibroblast-targeting strategies in chronic inflammation.
- Published
- 2023
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7. Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.
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Morille J, Mandon M, Rodriguez S, Roulois D, Leonard S, Garcia A, Wiertlewski S, Le Page E, Berthelot L, Nicot A, Mathé C, Lejeune F, Tarte K, Delaloy C, Amé P, Laplaud D, and Michel L
- Subjects
- Humans, B-Lymphocytes, Lymphocyte Activation, Lymphocyte Count, T-Box Domain Proteins metabolism, Th1 Cells, Multiple Sclerosis pathology, T-Lymphocytes, Helper-Inducer metabolism, T-Lymphocytes, Helper-Inducer pathology
- Abstract
Background and Objectives: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS)., Methods: The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event., Results: The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1
+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis., Discussion: Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2022
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8. CD40L-expressing CD4 + T cells prime adipose-derived stromal cells to produce inflammatory chemokines.
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Dulong J, Loisel S, Rossille D, Léonard S, Bescher N, Bezier I, Latour M, Monvoisin C, Monnier D, Bertheuil N, Roulois D, and Tarte K
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- Adipose Tissue, CD4-Positive T-Lymphocytes metabolism, Cells, Cultured, Chemokines metabolism, Humans, Interleukin-8 metabolism, Obesity, Stromal Cells pathology, T-Lymphocytes, Tumor Necrosis Factor-alpha metabolism, CD40 Ligand genetics, CD40 Ligand metabolism, NF-kappa B metabolism
- Abstract
The therapeutic potential of culture-adapted adipose-derived stromal cells (ASCs) is largely related to their production of immunosuppressive factors that are inducible in vitro by priming with inflammatory stimuli, in particular tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ). In vivo, obesity is associated with chronic inflammation of white adipose tissue, including accumulation of neutrophils, infiltration by IFNγ/TNFα-producing immune cells, and ASC dysfunction. In the current study, we identified in obese patients a simultaneous upregulation of CD40Lin the adipose tissue stroma vascular fraction (AT-SVF), correlated with the Th1 gene signature, and an overexpression of CD40 by native ASCs. Moreover, activated CD4
+ T cells upregulated CD40 on culture-expanded ASCs and triggered their production of IL-8 in a CD40L-dependent manner, leading to an increased capacity to recruit neutrophils. Finally, activation of ASCs by sCD40L or CD40L-expressing CD4+ T cells relies on both canonical and non-canonical NF-κB pathways, and IL-8 was found to be coregulated with NF-κB family members in AT-SVF. These data identify the CD40-CD40L axis as a priming mechanism of ASCs, able to modulate their cross talk with neutrophils in an inflammatory context, and their functional capacity for therapeutic applications., Competing Interests: Conflict-of-interest Disclosure Authors have no competing interests to declare., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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9. Follicular lymphoma triggers phenotypic and functional remodeling of the human lymphoid stromal cell landscape.
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Mourcin F, Verdière L, Roulois D, Amin R, Lamaison C, Sibut V, Thamphya B, Pangault C, Monvoisin C, Huet S, Seffals M, Baulande S, Mechta-Grigoriou F, Legoix P, Rossille D, Guirriec M, Léonard S, Cartron G, Salles G, Fest T, and Tarte K
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- Cells, Cultured, Chemokine CCL19 metabolism, Chemokine CCL21 metabolism, Humans, Integrin alpha1 metabolism, Palatine Tonsil cytology, Signal Transduction immunology, Stromal Cells cytology, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, B-Lymphocytes immunology, Dendritic Cells immunology, Lymphoma, Follicular immunology, Lymphoma, Follicular pathology, Palatine Tonsil immunology, Stromal Cells immunology
- Abstract
Lymphoid stromal cells (LSCs) are essential organizers of immune responses. We analyzed tonsillar tissue by combining flow cytometry, in situ imaging, RNA sequencing, and functional assays, defining three distinct human LSC subsets. The integrin CD49a designated perivascular stromal cells exhibiting features of local committed LSC precursors and segregated cytokine and chemokine-producing fibroblastic reticular cells (FRCs) supporting B and T cell survival. The follicular dendritic cell transcriptional profile reflected active responses to B cell and non-B cell stimuli. We therefore examined the effect of B cell stimuli on LSCs in follicular lymphoma (FL). FL B cells interacted primarily with CD49a
+ FRCs. Transcriptional analyses revealed LSC reprogramming in situ downstream of the cytokines tumor necrosis factor (TNF) and transforming growth factor β (TGF-β), including increased expression of the chemokines CCL19 and CCL21. Our findings define human LSC populations in healthy tissue and reveal bidirectional crosstalk between LSCs and malignant B cells that may present a targetable axis in lymphoma., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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10. Extracellular vesicles shed by follicular lymphoma B cells promote polarization of the bone marrow stromal cell niche.
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Dumontet E, Pangault C, Roulois D, Desoteux M, Léonard S, Marchand T, Latour M, Legoix P, Loew D, Dingli F, Dulong J, Flecher E, Coulouarn C, Cartron G, Fest T, and Tarte K
- Subjects
- Base Sequence, Bone Marrow Cells metabolism, Cell Communication, Cell Differentiation, Endocytosis, Extracellular Vesicles metabolism, Extracellular Vesicles ultrastructure, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hematopoietic Stem Cells metabolism, Humans, Lymphoma, Follicular genetics, Lymphotoxin alpha1, beta2 Heterotrimer metabolism, Mesenchymal Stem Cells metabolism, Phenotype, Signal Transduction, Stromal Cells metabolism, Stromal Cells pathology, Tumor Necrosis Factor-alpha metabolism, Up-Regulation genetics, B-Lymphocytes pathology, Bone Marrow Cells pathology, Cell Polarity, Extracellular Vesicles pathology, Lymphoma, Follicular pathology
- Abstract
Follicular lymphoma (FL) originates in the lymph nodes (LNs) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSCs) obtained from FL BM display a specific gene expression profile (GEP), including enrichment for a lymphoid stromal cell signature, and an increased capacity to sustain FL B-cell growth. However, the mechanisms triggering the formation of the medullar FL permissive stromal niche have not been identified. In the current work, we demonstrate that FL B cells produce extracellular vesicles (EVs) that can be internalized by BM-MSCs, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activate transforming growth factor β-dependent and independent pathways in BM-MSCs and modify their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 and angiopoietin-1. Moreover, we provide the first characterization of BM FL B-cell GEP, allowing the definition of the landscape of molecular interactions they could engage with EV-primed BM-MSCs. This work identifies FL-derived EVs as putative mediators of BM stroma polarization and supports further investigation of their clinical interest for targeting the crosstalk between BM-MSCs and malignant B cells., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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11. DNA hypomethylating agents increase activation and cytolytic activity of CD8 + T cells.
- Author
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Loo Yau H, Bell E, Ettayebi I, de Almeida FC, Boukhaled GM, Shen SY, Allard D, Morancho B, Marhon SA, Ishak CA, Gonzaga IM, da Silva Medina T, Singhania R, Chakravarthy A, Chen R, Mehdipour P, Pommey S, Klein C, Amarante-Mendes GP, Roulois D, Arribas J, Stagg J, Brooks DG, and De Carvalho DD
- Subjects
- DNA Methylation immunology, Humans, NFATC Transcription Factors immunology, Perforin immunology, CD8-Positive T-Lymphocytes immunology, CpG Islands immunology, DNA Methylation drug effects, Decitabine pharmacology, Granzymes immunology, Lymphocyte Activation drug effects
- Abstract
We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8
+ T cells. In vivo HMA treatment promotes CD8+ T cell tumor infiltration and suppresses tumor growth via CD8+ T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8+ T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8+ T cell subpopulations, increasing both the number and abundance of a granzyme Bhigh , perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response., Competing Interests: Declaration of interests D.D.D.C. received research funds from Pfizer and Nektar Therapeutics. D.D.D.C. is a co-founder and shareholder of DNAMx, Inc. C.K. is employed by and owns stock, patents, and royalties with Roche. J.S. is a permanent scientific advisory board member for and owns stock in Surface Oncology., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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12. Integrated transcriptomic, phenotypic, and functional study reveals tissue-specific immune properties of mesenchymal stromal cells.
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Ménard C, Dulong J, Roulois D, Hébraud B, Verdière L, Pangault C, Sibut V, Bezier I, Bescher N, Monvoisin C, Gadelorge M, Bertheuil N, Flécher E, Casteilla L, Collas P, Sensebé L, Bourin P, Espagnolle N, and Tarte K
- Subjects
- Adult, Cell Differentiation, Cells, Cultured, Female, Humans, Male, Middle Aged, Phenotype, Young Adult, Mesenchymal Stem Cells metabolism, Transcriptome genetics
- 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., (© AlphaMed Press 2019.)
- Published
- 2020
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13. Epigenetic mechanisms driving tumor supportive microenvironment differentiation and function: a role in cancer therapy?
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Sylvestre M, Tarte K, and Roulois D
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- Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cancer-Associated Fibroblasts metabolism, Humans, Immune Tolerance, Neoplasms drug therapy, Neoplasms immunology, Neoplasms metabolism, Epigenesis, Genetic drug effects, Gene Expression Regulation, Neoplastic, Neoplasms genetics, Tumor Microenvironment drug effects
- Abstract
The tumor microenvironment (TME) plays a central role in tumor development and drug resistance. Within TME, the stromal cell subset, called cancer-associated fibroblasts, is a heterogeneous population originating from poorly characterized precursors. Since cancer-associated fibroblasts do not acquire somatic mutations, other mechanisms like epigenetic regulation, could be involved in the development of these cells and in the acquisition of tumor supportive phenotypes. Moreover, such epigenetic modulations have been correlated to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. These findings underline the need to deepen our knowledge on epigenetic mechanisms driving TME development and function, and to understand the impact of epigenetic drugs that could be used in future to target both tumor cells and their TME.
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- 2020
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14. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.
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Nayar S, Campos J, Smith CG, Iannizzotto V, Gardner DH, Mourcin F, Roulois D, Turner J, Sylvestre M, Asam S, Glaysher B, Bowman SJ, Fearon DT, Filer A, Tarte K, Luther SA, Fisher BA, Buckley CD, Coles MC, and Barone F
- Subjects
- Animals, Disease Models, Animal, Flow Cytometry, Fluorescent Antibody Technique, Humans, Interleukin-13 metabolism, Interleukins metabolism, Lymphocytes pathology, Mice, Salivary Glands pathology, Interleukin-22, Fibroblasts pathology, Tertiary Lymphoid Structures pathology
- Abstract
Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
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15. Sensitive tumour detection and classification using plasma cell-free DNA methylomes.
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Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, Zuzarte PC, Borgida A, Wang TT, Li T, Kis O, Zhao Z, Spreafico A, Medina TDS, Wang Y, Roulois D, Ettayebi I, Chen Z, Chow S, Murphy T, Arruda A, O'Kane GM, Liu J, Mansour M, McPherson JD, O'Brien C, Leighl N, Bedard PL, Fleshner N, Liu G, Minden MD, Gallinger S, Goldenberg A, Pugh TJ, Hoffman MM, Bratman SV, Hung RJ, and De Carvalho DD
- Subjects
- Adenocarcinoma blood, Adenocarcinoma genetics, Animals, Biomarkers, Tumor genetics, Cell Line, Tumor, Colorectal Neoplasms blood, Colorectal Neoplasms genetics, DNA Mutational Analysis, Epigenesis, Genetic, Female, Heterografts, Humans, Liquid Biopsy, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Neoplasms blood, Organ Specificity, Pancreatic Neoplasms blood, Pancreatic Neoplasms genetics, Cell-Free Nucleic Acids blood, Cell-Free Nucleic Acids metabolism, DNA Methylation, DNA, Neoplasm blood, DNA, Neoplasm metabolism, Early Detection of Cancer methods, Neoplasms classification, Neoplasms genetics
- Abstract
The use of liquid biopsies for cancer detection and management is rapidly gaining prominence
1 . Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5 . By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.- Published
- 2018
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16. Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine.
- Author
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Roulois D, Deshayes S, Guilly MN, Nader JS, Liddell C, Robard M, Hulin P, Ouacher A, Le Martelot V, Fonteneau JF, Grégoire M, Blanquart C, and Pouliquen DL
- Subjects
- 5-Methylcytosine metabolism, Animals, Asbestos, Crocidolite toxicity, Biomarkers, Tumor, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p16, DNA Methyltransferase 3A, Epithelial Cells pathology, Epithelium pathology, Humans, Karyotype, Lung Neoplasms chemically induced, Mesothelioma chemically induced, Mesothelioma, Malignant, Rats, Rats, Inbred F344, 5-Methylcytosine analogs & derivatives, Cell Transformation, Neoplastic pathology, Cyclin-Dependent Kinase Inhibitor p18 metabolism, DNA (Cytosine-5-)-Methyltransferases metabolism, Lung Neoplasms pathology, Mesothelioma pathology, Mixed Function Oxygenases metabolism, Precancerous Conditions pathology, Proto-Oncogene Proteins metabolism
- Abstract
Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome, urging the need to establish and characterize new preclinical tools for investigation of the tumorigenic process, improvement of early diagnosis and evaluation of new therapeutic strategies. For these purposes, we characterized a collection of 27 cell lines established from F344 rats, after 136 to 415 days of induction with crocidolite asbestos administered intraperitoneally. Four mesotheliomas were distinguished from 23 preneoplastic mesothelial cell lines (PN) according to their propensity to generate tumors after orthotopic transplantation into syngeneic rats, their growth pattern, and the expression profile of three genes. PN cell lines were further discriminated into groups / subgroups according to morphology in culture and the expression profiles of 14 additional genes. This approach was completed by analysis of positive and negative immunohistochemical MM markers in the four tumors, of karyotype alterations in the most aggressive MM cell line in comparison with a PN epithelioid cell line, and of human normal mesothelial and mesothelioma cells and a tissue array. Our results showed that both the rat and human MM cell lines shared in common a dramatic decrease in the relative expression of Cdkn2a and of epigenetic regulators, in comparison with PN and normal human mesothelial cells, respectively. In particular, we identified the involvement of the relative expression of the Ten-Eleven Translocation (TET) family of dioxygenases and Dnmt3a in relation to the 5-hydroxymethylcytosine level in malignant transformation and the acquisition of metastatic potential., Competing Interests: The authors declare that they have no competing interests.
- Published
- 2016
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17. Pre-neoplastic epigenetic disruption of transcriptional enhancers in chronic inflammation.
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Planello AC, Singhania R, Kron KJ, Bailey SD, Roulois D, Lupien M, Line SR, de Souza AP, and De Carvalho DD
- Subjects
- Adult, Carcinoma, Squamous Cell genetics, DNA Methylation, Epigenesis, Genetic, Female, Head and Neck Neoplasms genetics, Humans, Inflammation complications, Male, Mouth Neoplasms genetics, Squamous Cell Carcinoma of Head and Neck, Chronic Periodontitis genetics, Enhancer Elements, Genetic genetics, Inflammation genetics, Precancerous Conditions genetics
- Abstract
Chronic periodontitis (CP) is a chronic inflammatory disease independently associated with higher incidence of oral cavity squamous cell carcinoma (OSCC). However, the molecular mechanism responsible for this increased incidence is unknown. Here we profiled the DNA methylome of CP patients and healthy controls and compared to a large set of OSCC samples from TCGA. We observed a significant overlap between the altered DNA methylation patterns in CP and in OSCC, suggesting an emergence of a pre-neoplastic epigenome in CP. Remarkably, the hypermethylated CpGs in CP were significantly enriched for enhancer elements. This aberrant enhancer methylation is functional and able to disrupt enhancer activity by preventing the binding of chromatin looping factors. This study provides new insights on the molecular mechanisms linking chronic inflammation and tumor predisposition, highlighting the role of epigenetic disruption of transcriptional enhancers.
- Published
- 2016
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18. Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response.
- Author
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Achard C, Boisgerault N, Delaunay T, Roulois D, Nedellec S, Royer PJ, Pain M, Combredet C, Mesel-Lemoine M, Cellerin L, Magnan A, Tangy F, Grégoire M, and Fonteneau JF
- Subjects
- Antigens, CD metabolism, Cell Adhesion Molecules metabolism, Cell Line, Tumor, Host-Pathogen Interactions, Humans, Interferon Type I immunology, Measles virus immunology, Measles virus metabolism, Membrane Cofactor Protein metabolism, Mesothelioma immunology, Mesothelioma metabolism, Mesothelioma virology, Oncolytic Viruses immunology, Oncolytic Viruses metabolism, Pleural Neoplasms immunology, Pleural Neoplasms metabolism, Pleural Neoplasms virology, Receptors, Cell Surface metabolism, Signal Transduction, Signaling Lymphocytic Activation Molecule Family Member 1, Time Factors, Interferon Type I metabolism, Measles virus growth & development, Mesothelioma therapy, Oncolytic Virotherapy methods, Oncolytic Viruses growth & development, Pleural Neoplasms therapy, Virus Replication
- Abstract
Attenuated measles virus (MV) is currently being evaluated as an oncolytic virus in clinical trials and could represent a new therapeutic approach for malignant pleural mesothelioma (MPM). Herein, we screened the sensitivity to MV infection and replication of twenty-two human MPM cell lines and some healthy primary cells. We show that MV replicates in fifteen of the twenty-two MPM cell lines. Despite overexpression of CD46 by a majority of MPM cell lines compared to healthy cells, we found that the sensitivity to MV replication did not correlate with this overexpression. We then evaluated the antiviral type I interferon (IFN) responses of MPM cell lines and healthy cells. We found that healthy cells and the seven insensitive MPM cell lines developed a type I IFN response in presence of the virus, thereby inhibiting replication. In contrast, eleven of the fifteen sensitive MPM cell lines were unable to develop a complete type I IFN response in presence of MV. Finally, we show that addition of type I IFN onto MV sensitive tumor cell lines inhibits replication. These results demonstrate that defects in type I IFN response are frequent in MPM and that MV takes advantage of these defects to exert oncolytic activity.
- Published
- 2015
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19. Pharmacological DNA demethylation: Implications for cancer immunotherapy.
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Roulois D, Yau HL, and De Carvalho DD
- Abstract
Recent studies have demonstrated that DNA demethylation agents can mimic a viral infection by induction of dsRNAs. This viral mimicry leads to an antiviral response mediated by the cytosolic pattern recognition receptor MDA5, followed by MAVS (IPS1) activation, IRF7 nuclear translocation and upregulation of type III Interferon and interferon-stimulated genes.
- Published
- 2015
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20. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts.
- Author
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Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, Han H, Liang G, Jones PA, Pugh TJ, O'Brien C, and De Carvalho DD
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Azacitidine pharmacology, Cells, Cultured, DEAD-box RNA Helicases metabolism, DNA Methylation drug effects, Decitabine, Endogenous Retroviruses metabolism, Humans, Interferon Regulatory Factor-7 metabolism, Interferon-Induced Helicase, IFIH1, Mice, RNA, Double-Stranded metabolism, Receptors, Retinoic Acid metabolism, Signal Transduction, Antimetabolites, Antineoplastic pharmacology, Azacitidine analogs & derivatives, Colorectal Neoplasms drug therapy, Colorectal Neoplasms immunology
- Abstract
DNA-demethylating agents have shown clinical anti-tumor efficacy via an unknown mechanism of action. Using a combination of experimental and bioinformatics analyses in colorectal cancer cells, we demonstrate that low-dose 5-AZA-CdR targets colorectal cancer-initiating cells (CICs) by inducing viral mimicry. This is associated with induction of dsRNAs derived at least in part from endogenous retroviral elements, activation of the MDA5/MAVS RNA recognition pathway, and downstream activation of IRF7. Indeed, disruption of virus recognition pathways, by individually knocking down MDA5, MAVS, or IRF7, inhibits the ability of 5-AZA-CdR to target colorectal CICs and significantly decreases 5-AZA-CdR long-term growth effects. Moreover, transfection of dsRNA into CICs can mimic the effects of 5-AZA-CdR. Together, our results represent a major shift in understanding the anti-tumor mechanisms of DNA-demethylating agents and highlight the MDA5/MAVS/IRF7 pathway as a potentially druggable target against CICs., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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21. Measles virus vaccine-infected tumor cells induce tumor antigen cross-presentation by human plasmacytoid dendritic cells.
- Author
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Guillerme JB, Boisgerault N, Roulois D, Ménager J, Combredet C, Tangy F, Fonteneau JF, and Gregoire M
- Subjects
- Blotting, Western, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes virology, Cell Proliferation, Cells, Cultured, Dendritic Cells metabolism, Dendritic Cells virology, Fluorescent Antibody Technique, Humans, Interferon-alpha metabolism, Interleukin-3 pharmacology, Membrane Cofactor Protein immunology, Membrane Cofactor Protein metabolism, Neoplasms therapy, Neoplasms virology, RNA, Messenger genetics, RNA, Viral genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptor 7 metabolism, Antigens, Neoplasm immunology, Cross-Priming immunology, Dendritic Cells immunology, Measles Vaccine pharmacology, Neoplasms immunology, Oncolytic Virotherapy, Phagocytosis immunology
- Abstract
Purpose: Plasmacytoid dendritic cells (pDC) are antigen-presenting cells specialized in antiviral response. The measles virus vaccine is proposed as an antitumor agent to target and specifically kill tumor cells without infecting healthy cells., Experimental Design: Here, we investigated, in vitro, the effects of measles virus vaccine-infected tumor cells on the phenotype and functions of human pDC. We studied maturation and tumor antigen cross-presentation by pDC, exposed either to the virus alone, or to measles virus vaccine-infected or UV-irradiated tumor cells., Results: We found that only measles virus vaccine-infected cells induced pDC maturation with a strong production of IFN-α, whereas UV-irradiated tumor cells were unable to activate pDC. This IFN-α production was triggered by the interaction of measles virus vaccine single-stranded RNA (ssRNA) with TLR7. We observed that measles virus vaccine-infected tumor cells were phagocytosed by pDC. Interestingly, we showed cross-presentation of the tumor antigen NYESO-1 to a specific CD8(+) T-cell clone when pDC were cocultured with measles virus vaccine-infected tumor cells, whereas pDC were unable to cross-present NYESO-1 after coculture with UV-irradiated tumor cells., Conclusions: Altogether, our results suggest that the use of measles virus vaccine in antitumor virotherapy induces immunogenic tumor cell death, allowing pDC to mature, produce high amounts of IFN-α, and cross-present tumor antigen, thus representing a mode of recruiting these antigen-presenting cells in the immune response. Clin Cancer Res; 19(5); 1147-58. ©2012 AACR., (©2012 AACR.)
- Published
- 2013
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22. MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge.
- Author
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Roulois D, Grégoire M, and Fonteneau JF
- Subjects
- Animals, Antigens, Neoplasm immunology, Antineoplastic Agents pharmacology, Cancer Vaccines immunology, Cell Line, Tumor, Clinical Trials as Topic, Disease Models, Animal, HLA Antigens metabolism, Humans, Immunotherapy methods, Mice, Neoplasms immunology, T-Lymphocytes, Cytotoxic immunology, Gene Expression Regulation, Neoplastic, Mucin-1 metabolism, Neoplasms therapy, T-Lymphocytes, Cytotoxic cytology
- Abstract
MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.
- Published
- 2013
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23. Downregulation of MUC1 expression and its recognition by CD8⁺ T cells on the surface of malignant pleural mesothelioma cells treated with HDACi.
- Author
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Roulois D, Blanquart C, Panterne C, Gueugnon F, Grégoire M, and Fonteneau JF
- Subjects
- Antigens, Neoplasm immunology, Azacitidine pharmacology, Cell Line, Tumor, Decitabine, Down-Regulation drug effects, Down-Regulation immunology, Drug Therapy, Combination, Flow Cytometry, Humans, Kinetics, Membrane Proteins immunology, Mesothelioma drug therapy, Mesothelioma genetics, Mucin-1 genetics, RNA chemistry, RNA genetics, Real-Time Polymerase Chain Reaction, Statistics, Nonparametric, Azacitidine analogs & derivatives, CD8-Positive T-Lymphocytes immunology, Histone Deacetylase Inhibitors pharmacology, Mesothelioma immunology, Mucin-1 immunology, Valproic Acid pharmacology
- Abstract
Research into new treatments against malignant pleural mesothelioma (MPM) is of great interest, as this aggressive cancer is often resistant to conventional therapies. One potential strategy is the use of epigenetic drugs, such as 5-aza-2'-deoxycytidine (5-azaCdR), a DNA-hypomethylating drug, and valproate (VPA), a histone deacetylase inhibitor (HDACi). Indeed, these drugs not only trigger MPM cell death, but also induce the expression of cancer testis antigens recognized by CD8(+) T cells, such as New York-esophageal cancer-1 (NY-ESO-1). The objective of this study was to assess effects of these drugs on the expression and recognition by CD8(+) T cells of Mucin1 (MUC1), a tumor-associated antigen that is overexpressed by MPM. MPM tumor cell lines were treated with epigenetic drugs, alone or in combination. MUC1 expression by MPM cells, and its recognition by a MUC1-specific CD8(+) T-cell clone, was downregulated by HDACi when used alone or in combination with 5-azaCdR. This effect was not due to a blocking of the HLA class I presentation pathway in treated MPM cells, as NY-ESO-1 induced by 5-azaCdR alone, or with VPA, was recognized by a NY-ESO-1-specific T-cell clone. This study suggests that the choice of tumor antigens could be critical for strategies combining epigenetic drugs with immunotherapy., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
- Full Text
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