title: A novel tumor-associated pancreatic glycoprotein is internalized by human dendritic cells and induces their maturation.
abstract: Aberrant glycosylation or overexpression of cell-surface glycosylated tumor-associated Ags (TAA) distinguish neoplastic from normal cells. Interactions of TAA MUC1 and HER2/neu with dendritic cells (DC) preclude efficient processing, which impairs immune responses. It is thus important to define the mechanisms of interactions between DC and glycosylated TAA and their trafficking and processing for further T cell activation. In this work, we study interactions between DC and the oncofetal fucose-rich glycovariants of bile salt-dependent lipase (BSDL), expressed in pancreatic cancer tissues and referred to as pathological BSDL carrying the fucosylated J28 glycotope (pBSDL-J28) because it is characterized by the mAb J28. The expression of pBSDL-J28 was assessed by immunohistochemistry and quantified by confocal microscopy. Nontumoral pancreatic tissues and cells do not express pBSDL-J28. Using multidisciplinary approaches and functional studies, we provide the first evidence, to our knowledge, that this tumoral glycoprotein is rapidly internalized by human DC through macropinocytosis and endocytosis via mannose receptors and then transported to late endosomes for processing. Interestingly, pBSDL-J28 per se induced DC maturation with increased expression of costimulatory and CD83 molecules associated with cytokine secretion (IL-8 and IL-6). Surprisingly, DC retained their full ability to internalize Ags, making this maturation atypical. Finally, the allogeneic pBSDL-J28-treated DC stimulated lymphocyte proliferation. Besides, pulsing DC with pBSDL-J28 C-terminal glycopolypeptide and maturation with CD40L triggered CD4(+) and CD8(+) T cell proliferation. Therefore, interactions of pBSDL-J28, expressed on tumoral pancreatic tissue, with DC may lead to adequate Ag trafficking and processing and result in T cell activation.
authors.affiliation: INSERM Unité Mixte de Recherche 911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, F-13005 Marseille, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Franceschi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Collignon
authors.forename: Daniel
authors.initials: D
authors.lastname: Isnardon
authors.forename: Liliane
authors.initials: L
authors.lastname: Benkoel
authors.forename: Alain
authors.initials: A
authors.lastname: Vérine
authors.forename: Françoise
authors.initials: F
authors.lastname: Silvy
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bernard
authors.forename: Dominique
authors.initials: D
authors.lastname: Lombardo
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beraud
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Eric
authors.initials: E
authors.lastname: Mas
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000378:metabolism* / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism; D002787:Sterol Esterase / Q000378:metabolism* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C054784:bile salt-stimulated lipase; D002787:Sterol Esterase