title: Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells.
abstract: Tumors exploit several strategies to evade immune recognition, including the production of a large number of immunosuppressive factors, which leads to reduced numbers and impaired functions of dendritic cells (DCs) in the vicinity of tumors. We have investigated whether a mucin released by tumor cells could be involved in causing these immunomodulating effects on DCs. We used a recombinant purified form of the MUC1 glycoprotein, an epithelial associated mucin that is overexpressed, aberrantly glycosylated, and shed during cancer transformation. The O-glycosylation profile of the recombinant MUC1 glycoprotein (ST-MUC1) resembled that expressed by epithelial tumors in vivo, consisting of large numbers of sialylated core 1 (sialyl-T, ST) oligosaccharides. When cultured in the presence of ST-MUC1, human monocyte-derived DCs displayed a modified phenotype with decreased expression of costimulatory molecules (CD86, CD40), Ag-presenting molecules (DR and CD1d), and differentiation markers (CD83). In contrast, markers associated with an immature phenotype, CD1a and CD206 (mannose receptor), were increased. This effect was already evident at day 4 of DC culture and was dose dependent. The modified phenotype of DCs corresponded to an altered balance in IL-12/IL-10 cytokine production, with DC expressing an IL-10(high)IL-12(low) phenotype after exposure to ST-MUC1. These DCs were defective in their ability to induce immune responses in both allogeneic and autologous settings, as detected in proliferation and ELISPOT assays. The altered DC differentiation and Ag presentation function induced by the soluble sialylated tumor-associated mucin may represent a mechanism by which epithelial tumors can escape immunosurveillance.
authors.affiliation: Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Rughetti
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pellicciotta
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.forename: Malin
authors.initials: M
authors.lastname: Bäckström
authors.forename: Thomas
authors.initials: T
authors.lastname: Link
authors.forename: Eric P
authors.initials: EP
authors.lastname: Bennet
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.forename: Thomas
authors.initials: T
authors.lastname: Noll
authors.forename: Gunnar C
authors.initials: GC
authors.lastname: Hansson
authors.forename: Joy M
authors.initials: JM
authors.lastname: Burchell
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Joyce
authors.initials: J
authors.lastname: Taylor-Papadimitriou
authors.forename: Marianna
authors.initials: M
authors.lastname: Nuti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D016466:CHO Cells; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006031:Glycosylation; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D019158:N-Acetylneuraminic Acid