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1. Activated B-Cells enhance epitope spreading to support successful cancer immunotherapy

Author

Guillaume Kellermann, Nicolas Leulliot, Julien Cherfils-Vicini, Magali Blaud, and Patrick Brest

Subjects
B-cell, tolerance, immunotherapy, epitope spreading, RNA binding protein, Immunologic diseases. Allergy, RC581-607
Abstract

Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful immunotherapy requires epitope spreading, but the slow or inefficient induction of functional antitumoral immunity delays the benefit to patients or causes resistances. Therefore, understanding the key mechanisms that support epitope spreading is essential to improve immunotherapy. In this review, we highlight the major role played by B-cells in breaking immune tolerance by epitope spreading. Activated B-cells are key Antigen-Presenting Cells (APC) that diversify the T-cell response against self-antigens, such as ribonucleoproteins, in autoimmunity but also during successful cancer immunotherapy. This has important implications for the design of future cancer vaccines.

Published
2024
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2. Platinum Complexes Can Bind to Telomeres by Coordination

Author

Lina Saker, Samar Ali, Caroline Masserot, Guillaume Kellermann, Joel Poupon, Marie-Paule Teulade-Fichou, Evelyne Ségal-Bendirdjian, and Sophie Bombard

Subjects
telomeres, platinum complexes, cisplatin, G-quadruplex, TRF2, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.

Published
2018
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3. Platinum Complexes Can Bind to Telomeres by Coordination

Author

Marie-Paule Teulade-Fichou, Caroline Masserot, Guillaume Kellermann, Samar Ali, Joël Poupon, Sophie Bombard, Lina Saker, Evelyne Ségal-Bendirdjian, Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives (U1007), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Hôpital Lariboisière, Conception, Synthèse et Vectorisation de Biomolécules, Université Paris-Sud - Paris 11 (UP11)-Institut Curie-UMR 176-CNRS-le Laboratoire Raymond-Latarget d'Orsay, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11)-UMR 176-CNRS-le Laboratoire Raymond-Latarget d'Orsay-Institut Curie [Paris], and Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Programmed cell death, chemistry.chemical_element, cisplatin, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, TRF2, G-quadruplex, Catalysis, Article, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, medicine, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Uncapping, Platinum, Cisplatin, Molecular Structure, Organic Chemistry, General Medicine, Telomere, telomeres, In vitro, Computer Science Applications, G-Quadruplexes, genomic DNA, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, chemistry, Biophysics, medicine.drug, platinum complexes
Abstract

International audience; It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.

Published
2018

4. Exploring the mechanism of inhibition of human telomerase by cysteine-reactive compounds

Author

Evelyne Ségal-Bendirdjian, Daniel Dauzonne, Marie-Paule Teulade-Fichou, Vanessa Masson, Florent Dingli, Guillaume Kellermann, Damarys Loew, and Sophie Bombard

Subjects
0301 basic medicine, Models, Molecular, Telomerase, Biophysics, Biochemistry, Mass Spectrometry, law.invention, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Protein Domains, Structural Biology, law, Genetics, Humans, Telomerase reverse transcriptase, Amino Acid Sequence, Cysteine, Molecular Biology, chemistry.chemical_classification, Binding Sites, Molecular Structure, Sequence Homology, Amino Acid, Mutagenesis, RNA, Cell Biology, Recombinant Proteins, 030104 developmental biology, Enzyme, chemistry, 030220 oncology & carcinogenesis, Recombinant DNA, Reverse Transcriptase Inhibitors, Function (biology), Protein Binding
Abstract

Telomerase is an almost universal cancer target that consists minimally of a core protein human telomerase reverse transcriptase (hTERT) and a RNA component human telomerase RNA (hTR). Some inhibitors of this enzyme are thought to function by the covalent binding to one or several cysteine residues; however, this inhibition mechanism has never been investigated because of the difficulty in producing telomerase. In this study, we use a recent method to produce recombinant hTERT to analyze the effect of cysteine-reactive inhibitors on telomerase. Using mass spectrometry and mutagenesis analysis, we identify several targeted residues in separated domains of the hTERT protein and show that cysteine-reactive reagents abolish the interaction with the CR4/5 region of hTR.

Published
2016

5. Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting

Author

Angela Marinetti, Samar Ali, Marie-Paule Teulade-Fichou, Jean-François Betzer, Florian Hamon, Mélanie Chtchigrovsky, Frédérick Nuter, Joël Poupon, Sylvain Roque, Sophie Bombard, Marie-Ange Calméjane, Thierry Cresteil, Guillaume Kellermann, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives (U1007), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), BETZER, Jean-Francois, and Institut de Chimie du CNRS (INC)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]

Subjects
0301 basic medicine, Organoplatinum Compounds, Stereochemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Biomedical Engineering, Pharmaceutical Science, Antineoplastic Agents, Bioengineering, macromolecular substances, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Ligands, G-quadruplex, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Humans, Moiety, Telomeric Repeat Binding Protein 2, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Cell Proliferation, Pharmacology, Genetics, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Stereoisomerism, hemic and immune systems, DNA, Telomere, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Ligand (biochemistry), [CHIM.ORGA] Chemical Sciences/Organic chemistry, Small molecule, In vitro, G-Quadruplexes, Protein Transport, 030104 developmental biology, Biotechnology, Conjugate
Abstract

International audience; G-quadruplex structures (G4) are promising anticancer-ous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4-binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene−platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively.

Published
2016

6. Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

Author

Yann Godet, Claire André, Laurent Beziaud, Marine Jary, Laura Boullerot, Emilie Picard, Yves Claude Guillaume, Lydie Lethier, Guillaume Kellermann, Romain Boidot, Laura Mansi, Christophe Borg, Lise Queiroz, Olivier Adotevi, Jeanne Galaine, Evelyne Ségal-Bendirdjian, Romain Loyon, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives (U1007), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie Analytique Bioanalytique et Physique [CHU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Chimiothérapie et réponse immunitaire anti-tumorale (U866, Cancer, équipe 1), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Paris Descartes - Paris 5 (UPD5), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Inserm UMR 1098, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Centre d'Investigation Clinique de Besançon (CICB), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang Bourgogne Franche-Comté-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives ( U1007 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre d'Investigation Clinique de Besançon ( CICB ), Etablissement Français du Sang Bourgogne Franche-Comté-Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire Chrono-environnement - UFC (UMR 6249) ( LCE ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 )

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, Telomerase, Direct tumor recognition, Identification, media_common.quotation_subject, medicine.medical_treatment, Immunology, Antigen presentation, Epitopes, T-Lymphocyte, Htert, Expression, Antitumor immune-responses, Lymphocyte Activation, Epitope, Monocytes, IFN-gamma, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Humans, Telomerase reverse transcriptase, Internalization, cd4(+) t-cells, media_common, Cancer, MHC class II, Antigen Presentation, biology, Immunotherapy, Dendritic Cells, HLA-DR Antigens, Molecular biology, 3. Good health, Cell biology, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Peptides, Heparan Sulfate Proteoglycans
Abstract

Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR–restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT’s uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well-characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT’s internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells.

Published
2015

7. Increased Engraftment of Hepatic Progenitors After Activation of the Hepatocyte Growth Factor Signaling Pathway by Protein Transduction

Author

Anne Weber, Michelle Hadchouel, Guillaume Kellermann, and Lyes Boudechiche

Subjects
Cell type, Hepatocyte Growth Factor, Stem Cells, Biology, Recombinant Proteins, General Biochemistry, Genetics and Molecular Biology, In vitro, Cell Line, Transplantation, Mice, Transduction (genetics), Cell surface receptor, Hepatocytes, Cancer research, medicine, Animals, Receptors, Growth Factor, tat Gene Products, Human Immunodeficiency Virus, Hepatocyte growth factor, Signal transduction, Progenitor cell, Signal Transduction, Stem Cell Transplantation, medicine.drug
Abstract

Cell transplantation has become a major focus in biomedical research. However, efficient engraftment in solid tissues remains a challenge. Hepatocyte growth factor (HGF) signaling increases survival, proliferation, migration, and invasion of many cell types through Met, its cell surface receptor. Therefore, activation of this signaling pathway may improve the ability of many cells to be transplanted. We constructed a constitutively activated form of Met (Tpr-Met) fused to the protein transduction domain of HIV-TAT to activate the HGF/Met pathway for a few hours following cell injection. Matrix-assisted refolding was used to renature TAT-Tpr-Met protein, which was efficiently delivered into cells and recapitulated several biological functions of Met in vitro. Furthermore, treatment of hepatic progenitors with this molecule for one hour before transplantation significantly improved engraftment efficiency (31% untreated cells, 58% treated cells). These findings suggest that the transient transfer of Tpr-Met may provide a new approach to increase the proportion of successfully engrafted cells.

Published
2009

8. Identification of human telomerase assembly inhibitors enabled by a novel method to produce hTERT

Author

Guillaume, Kellermann, Markus, Kaiser, Florent, Dingli, Olivier, Lahuna, Delphine, Naud-Martin, Florence, Mahuteau-Betzer, Damarys, Loew, Evelyne, Ségal-Bendirdjian, Marie-Paule, Teulade-Fichou, and Sophie, Bombard

Subjects
Niacinamide, RNA Folding, Recombinant Fusion Proteins, Small Molecule Libraries, Structure-Activity Relationship, Thiazoles, HEK293 Cells, Genetic Techniques, Acridines, Humans, RNA, Methods Online, Telomerase, Trisaccharides
Abstract

Telomerase is the enzyme that maintains the length of telomeres. It is minimally constituted of two components: a core reverse transcriptase protein (hTERT) and an RNA (hTR). Despite its significance as an almost universal cancer target, the understanding of the structure of telomerase and the optimization of specific inhibitors have been hampered by the limited amount of enzyme available. Here, we present a breakthrough method to produce unprecedented amounts of recombinant hTERT and to reconstitute human telomerase with purified components. This system provides a decisive tool to identify regulators of the assembly of this ribonucleoprotein complex. It also enables the large-scale screening of small-molecules capable to interfere with telomerase assembly. Indeed, it has allowed us to identify a compound that inhibits telomerase activity when added prior to the assembly of the enzyme, while it has no effect on an already assembled telomerase. Therefore, the novel system presented here may accelerate the understanding of human telomerase assembly and facilitate the discovery of potent and mechanistically unique inhibitors.

Published
2015

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