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J Immunol. 2016 Sep 1;197(5):1597-608. doi: 10.4049/jimmunol.1502633. Epub 2016 Aug 1.

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

Author information

1
INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France;
2
University of Paris Descartes, INSERM, UMR S1007, Paris Sorbonne Cité, 75270 Paris, France;
3
Laboratoire de Chimie Analytique Bioanalytique et Physique, Equipe d'Accueil 481, 25000 Besançon, France; Department of Pharmacy, University Hospital of Besançon, 25030 Besançon, France;
4
Platform of Transfer in Cancer Biology, Georges François Leclerc Center, INSERM, UMR 866, 21000 Dijon, France;
5
INSERM, UMR 1098, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France;
6
INSERM, UMR 1098, 25000 Besançon, France;
7
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.
8
Laboratoire de Chimie Analytique Bioanalytique et Physique, Equipe d'Accueil 481, 25000 Besançon, France;
9
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.
10
INSERM, UMR 1098, 25000 Besançon, France; University of Bourgogne Franche-Comté, 25000 Besançon, France; yann.godet@univ-fcomte.fr olivier.adotevi@univ-fcomte.fr.
11
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.

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.

PMID:
27481844
DOI:
10.4049/jimmunol.1502633
[Indexed for MEDLINE]
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