title: Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells.
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.
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France;
authors.forename: Jeanne
authors.initials: J
authors.lastname: Galaine
authors.affiliation: University of Paris Descartes, INSERM, UMR S1007, Paris Sorbonne Cité, 75270 Paris, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kellermann
authors.affiliation: Laboratoire de Chimie Analytique Bioanalytique et Physique, Equipe d'Accueil 481, 25000 Besançon, France; Department of Pharmacy, University Hospital of Besançon, 25030 Besançon, France;
authors.forename: Yves
authors.initials: Y
authors.lastname: Guillaume
authors.affiliation: Platform of Transfer in Cancer Biology, Georges François Leclerc Center, INSERM, UMR 866, 21000 Dijon, France;
authors.forename: Romain
authors.identifier: 0000-0001-9956-1737
authors.initials: R
authors.lastname: Boidot
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France;
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France;
authors.forename: Romain
authors.identifier: 0000-0001-8039-7893
authors.initials: R
authors.lastname: Loyon
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France;
authors.forename: Lise
authors.initials: L
authors.lastname: Queiroz
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France;
authors.forename: Laura
authors.initials: L
authors.lastname: Boullerot
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Beziaud
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25030 Besançon, France; and.
authors.forename: Marine
authors.identifier: 0000-0001-7502-7708
authors.initials: M
authors.lastname: Jary
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25030 Besançon, France; and.
authors.forename: Laura
authors.identifier: 0000-0001-6079-5085
authors.initials: L
authors.lastname: Mansi
authors.affiliation: Laboratoire de Chimie Analytique Bioanalytique et Physique, Equipe d'Accueil 481, 25000 Besançon, France;
authors.forename: Claire
authors.initials: C
authors.lastname: André
authors.affiliation: Laboratoire de Chimie Analytique Bioanalytique et Physique, Equipe d'Accueil 481, 25000 Besançon, France;
authors.forename: Lydie
authors.initials: L
authors.lastname: Lethier
authors.affiliation: University of Paris Descartes, INSERM, UMR S1007, Paris Sorbonne Cité, 75270 Paris, France;
authors.forename: Evelyne
authors.identifier: 0000-0001-9813-4880
authors.initials: E
authors.lastname: Ségal-Bendirdjian
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25030 Besançon, France; and Etablissement Français du Sang, UMR 1098, 25000 Besançon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France; yann.godet@univ-fcomte.fr olivier.adotevi@univ-fcomte.fr.
authors.forename: Yann
authors.initials: Y
authors.lastname: Godet
authors.affiliation: INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25030 Besançon, France; and yann.godet@univ-fcomte.fr olivier.adotevi@univ-fcomte.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Adotévi
mesh_terms: D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation; D009000:Monocytes; D010455:Peptides / Q000378:metabolism; D019098:Telomerase / Q000276:immunology / Q000378:metabolism*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D019812:Heparan Sulfate Proteoglycans; D010455:Peptides; C509186:TERT protein, human; D019098:Telomerase