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6 results on '"Laurent Deleurme"'

1. Single-hit genome editing optimized for maturation in B cells redirects their specificity toward tumor antigens

Author

Natsuko Ueda, Marine Cahen, Jenny Leonard, Laurent Deleurme, Stéphane Dreano, Christophe Sirac, Anne Galy, Jérôme Moreaux, Yannic Danger, and Michel Cogné

Subjects
Medicine, Science
Abstract

Abstract T-cell-based adoptive immunotherapy is a new pillar of cancer care. Tumor-redirected B cells could also contribute to therapy if their manipulation to rewire immunoglobulin (Ig) genes is mastered. We designed a single-chain Ig-encoding cassette (“scFull-Ig”) that redirects antigen specificity when inserted at a single position of the IgH locus. This design, which places combined IgH and IgL variable genes downstream of a pVH promoter, nevertheless preserves all Ig functional domains and the intrinsic mechanisms that regulate expression from the IgM B cell receptor (BCR) expression to Ig secretion, somatic hypermutation and class switching. This single-locus editing provides an efficient and safe strategy to both disrupt endogenous Ig expression and encode a new Ig paratope. As a proof of concept, the functionality of scFull BCR and/or secreted Ig was validated against two different classical human tumor antigens, HER2 and hCD20. Once validated in cell lines, the strategy was extended to primary B cells, confirming the successful engineering of BCR and Ig expression and the ability of scFull-Ig to undergo further class switching. These results further pave the way for future B cell-based adoptive immunotherapy and strategies to express a therapeutic mAb with a variety of switched H-chains that provide complementary functions.

Published
2024
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2. Corrigendum: Follicular lymphoma regulatory T-cell origin and function

Author

Stéphane Rodriguez, Mehdi Alizadeh, Claire Lamaison, Alexis Saintamand, Céline Monvoisin, Rachel Jean, Laurent Deleurme, Jose Ignacio Martin-Subero, Céline Pangault, Michel Cogné, Patricia Amé-Thomas, and Karin Tarte

Subjects
follicular regulatory T cells, follicular helper T cells, follicular lymphoma, regulatory T cells, TCR repertoire, Immunologic diseases. Allergy, RC581-607
Published
2024
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3. Follicular lymphoma regulatory T-cell origin and function

Author

Stéphane Rodriguez, Mehdi Alizadeh, Claire Lamaison, Alexis Saintamand, Céline Monvoisin, Rachel Jean, Laurent Deleurme, Jose Ignacio Martin-Subero, Céline Pangault, Michel Cogné, Patricia Amé-Thomas, and Karin Tarte

Subjects
follicular regulatory T cells, follicular helper T cells, follicular lymphoma, regulatory T cells, TCR repertoire, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionFollicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse.MethodsThe aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays.ResultsCD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. DiscussionAltogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.

Published
2024
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4. Human Lymphoid Stromal Cells Contribute to Polarization of Follicular T Cells Into IL-4 Secreting Cells

Author

Jan Misiak, Rachel Jean, Stéphane Rodriguez, Laurent Deleurme, Thierry Lamy, Karin Tarte, and Patricia Amé-Thomas

Subjects
IL-4, fibroblastic reticular cells, follicular T cells, T follicular helper cells, follicular lymphoma, Immunologic diseases. Allergy, RC581-607
Abstract

Fibroblastic reticular cells (FRCs) are the specialized lymphoid stromal cells initially identified as triggering T-cell recruitment and dynamic motion in secondary lymphoid organs. Interestingly, FRCs also display antigen presentation capacities and support lymphocyte survival. CXCR5+CD4+ follicular T cells are important players of B-cell maturation and antibody response. Our study reported that in vitro-differentiated FRC-like cells enhanced the growth of the whole CXCR5+CD4+ T-cell compartment, while enhancing IL-4 secretion specifically by the PD1dimCXCR5+CD4+ cell subset, in a Notch- and ICAM1/LFA1-dependent manner. In addition, we revealed that in follicular lymphoma (FL) tissues, previously identified as enriched for PD1hiCXCR5hiCD4+ mature follicular helper T cells, PD1dimCXCR5+CD4+ T cells displayed an enrichment for Notch and integrin gene signatures, and a Notch and ICAM-1-dependent overexpression of IL-4 compared to their non-malignant counterparts. These findings suggest that the crosstalk between FRCs and CXCR5+PD1dimCD4+ T cells may contribute to the FL IL-4 rich environment, thus providing new insights in FL lymphomagenesis.

Published
2020
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5. Single-cell profiling identifies clinically relevant interactions between tumor associated macrophages and blood endothelial cells in diffuse large B cell lymphoma

Author

Juliette Ferrant, Simon Le Gallou, Francine Padonou, Simon Léonard, Ilénia Papa, Céline Pangault, Anne Barthel, Vincent Launay, Guillaume Manson, Bénédicte Hoareau, Laurent Deleurme, Céline Monvoisin, Benoit Albaud, Nathalie Van Acker, Camille Laurent, Francisco Llamas-Gutierrez, Henri-Alexandre Michaud, Nathalie Bonnefoy, Thierry Pécot, Karin Tarte, and Mikael Roussel

Abstract

SummaryDiffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most common B-cell lymphomas and are characterized by a dynamic crosstalk between tumor B cells and a heterogeneous tumor-supportive microenvironment, including immune, endothelial, and stromal components. Although their impact on the pathogenesis and prognosis of B-cell lymphoma has been acknowledged for years, tumor-associated macrophages (TAM) have not been extensively explored in DLBCL and FL. Herein, we investigate mononuclear phagocytes (MNP) heterogeneity at the single cell level and their potential co-regulation with the stromal and endothelial compartments in B-cell lymphoma lymph nodes compared to reactive secondary lymphoid organs, using a combination of mass cytometry, single cell RNA sequencing, andin silicoapproaches. We reveal a co-regulation between TAM and blood endothelial cells (BEC) in lymphoma. Moreover, we identify a specific interaction between Annexin A1 (ANXA1)-expressing BEC and formyl-peptide receptors (FPR1/2)-expressing monocytes/macrophages in DLBCL, which we confirmin situby multiplex immunofluorescence and imaging mass cytometry. This crosstalk is associated to an immunosuppressive tumor microenvironment and an adverse prognosis in DLBCL.

Published
2022

6. A novel 3D culture model recapitulates primary FL B cell features and promotes their survival

Author

Valérie Le Morvan, Pierre Nassoy, Patricia Legoix, Céline Pangault, Simon Latour, Pierre Soubeyran, Laurence Bresson-Bepoldin, Frédéric Mourcin, Kevin Alessandri, Elise Dessauge, Martina Prochazkova-Carlotti, Julien Saint-Vanne, Lea Broca-Brisson, Nelson Hélaine, Karin Tarte, Jean-Philippe Merlio, Sylvain Baulande, Laurent Deleurme, Isabelle Mahouche, Laetitia Andrique, Céline Monvoisin, Gaëlle Recher, Christelle Dussert, Claire Lamaison, Marine Seffals, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), University of Toronto, Laboratoire Photonique, Numérique et Nanosciences (LP2N), Université de Bordeaux (UB)-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Université de Rennes (UR), Institut Curie [Paris], Plateforme de sequencage ICGEX, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, CHU Bordeaux [Bordeaux], This work was supported by INSERM, University of Bordeaux, Ligue Régionalecontre le Cancer (comités de Gironde, Charentes, Pyrénées, Landes), the FondationARC pour la Recherche sur le Cancer (Grant PGA1 RF20170205386), the InstitutNational du cancer (INCA AAP PNP-19-009), Emergence GSO Cancéropole, andSIRIC BRIO. S.L. is supported by Ligue Nationale contre le Cancer and C.L. is arecipient of a doctoral fellowship from the FHU CAMIn and LBB (Léa Broca-Brisson)of a master fellowship from CNRS GDR Imabio. J.S.V. is funded by the InfrastructureeCellFrance (ANR-11-INBS-005). The 3D capsules were obtained from the VoxCellOrganoïds Plateform, a service of the CNRS-INSERM and Bordeaux University -UMS TBMCore 3427. We thank Stéphanie Durand-Panteix for her technical supportwith transduction experiments. We thank Atika Zouine and Vincent Pitard fortechnical assistance at the Flow cytometry facility, CNRS UMS 3427, INSERM US005, Univ. Bordeaux, F-33000 Bordeaux, France. We acknowledge the BordeauxImaging Center, a service unit of the CNRS-INSERM and Bordeaux University,member of the national infrastructure France BioImaging supported by the FrenchResearch Agency (ANR-10-INBS-04). Cell sorting was performed at the Biosit FlowCytometry and Cell Sorting Facility CytomeTRI (UMS 6480 Biosit, Rennes, France).High-throughput sequencing has been performed by the ICGex NGS platform of theInstitut Curie supported by the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Génomique Consortium) from the ANR, by the ITMO-CANCER,and by the SiRIC-Curie program (SiRIC Grant INCa-DGOS-4654)., The authors are indebted to the Centre de Ressources Biologiques (CRB)-Santé (BB-0033-00056) of Rennes hospital for the processing of biological samples., ANR-11-INBS-0005,ECELLFRANCE,Développement d'une Plateforme Nationale pour la médecine régénératrice(2011), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), 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 ), Plateforme de Séquençage ADN haut débit [Institut Curie] (NGS - ICGex), H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 - Faculté de Médecine (UR1 Médecine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Université de Rennes (UNIV-RENNES), Chard-Hutchinson, Xavier, Infrastructures - Développement d'une Plateforme Nationale pour la médecine régénératrice - - ECELLFRANCE2011 - ANR-11-INBS-0005 - INBS - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID

Subjects
Stromal cell, Lymphoma, B-Cell, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], [SDV]Life Sciences [q-bio], Follicular lymphoma, neoplasms, lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, doxorubicin, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, alginates, [SDV.CAN] Life Sciences [q-bio]/Cancer, follicular lymphoma, immune system diseases, hemic and lymphatic diseases, b-lymphocytes, medicine, Tumor Microenvironment, antineoplastic agents, Humans, cancer, Doxorubicin, Cell encapsulation, B cell, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Chemistry, Lymphoma, Non-Hodgkin, Hematology, medicine.disease, In vitro, Lymphoma, b-cell lymphomas, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, bcl-2 protein, medicine.drug
Abstract

Non-Hodgkin B-cell lymphomas (B-NHL) mainly develop within lymph nodes as aggregates of tumor cells densely packed with their surrounding microenvironment, creating a tumor niche specific to each lymphoma subtypes. In vitro preclinical models mimicking biomechanical forces, cellular microenvironment, and 3D organization of B-cell lymphomas remain scarce, while all these parameters are key determinants of lymphomagenesis and drug resistance. Using a microfluidic method based on cell encapsulation inside permeable, elastic, and hollow alginate microspheres, we developed a new tunable 3D model incorporating lymphoma B cells, extracellular matrix (ECM), and/or tonsil stromal cells (TSC). Under 3D confinement, lymphoma B cells were able to form cohesive spheroids resulting from overexpression of ECM components. Moreover, lymphoma B cells and TSC dynamically formed self-organized 3D spheroids favoring tumor cell growth. 3D culture induced resistance to the classical chemotherapeutic agent doxorubicin, but not to the BCL2 inhibitor ABT-199, identifying this approach as a relevant in vitro model to assess the activity of therapeutic agents in B-NHL. RNA-sequence analysis highlighted the synergy of 3D, ECM, and TSC in upregulating similar pathways in malignant B cells in vitro than those overexpressed in primary lymphoma B cells in situ. Finally, our 3D model including ECM and TSC allowed long-term in vitro survival of primary follicular lymphoma B cells. In conclusion, we propose a new high-throughput 3D model mimicking lymphoma tumor niche and making it possible to study the dynamic relationship between lymphoma B cells and their microenvironment and to screen new anti-cancer drugs.

Published
2021

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