title: Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation.
abstract: Dendritic cells (DCs) sense the microenvironment through several types of receptors recognizing pathogen-associated molecular patterns. In particular, C-type lectins, expressed by distinct subsets of DCs, recognize and internalize specific carbohydrate antigen in a Ca(2+) -dependent manner. Targeting of these receptors is becoming an efficient strategy of delivering antigens in DC-based anticancer immunotherapy. Here we investigated the role of the macrophage galactose type C-lectin receptor (MGL), expressed by immature DCs (iDCs), as a molecular target for α-N-acetylgalactosamine (GalNAc or Tn)-carrying tumor-associated antigens to improve DC performance. MGL expressed by ex vivo-generated iDCs from healthy donors was engaged by a 60-mer MUC1(9Tn) -glycopeptide as a Tn-carrying tumor-associated antigen, and an anti-MGL antibody, as a specific MGL binder. We demonstrated that MGL engagement induced homotrimers and homodimers, triggering the phosphorylation of extracellular signal-regulated kinase 1,2 (ERK1,2) and nuclear factor-κB activation. Analysis of DC phenotype and function demonstrated that MGL engagement improved DC performance as antigen-presenting cells, promoting the upregulation of maturation markers, a decrease in phagocytosis, an enhancement of motility, and most importantly an increase in antigen-specific CD8(+)  T-cell activation. These results demonstrate that the targeting of MGL receptor on human DCs has an adjuvant effect and that this strategy can be used to design novel anticancer vaccines.
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Napoletano
authors.forename: Ilaria G
authors.initials: IG
authors.lastname: Zizzari
authors.forename: Aurelia
authors.initials: A
authors.lastname: Rughetti
authors.forename: Hassan
authors.initials: H
authors.lastname: Rahimi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.forename: Hans H
authors.initials: HH
authors.lastname: Wandall
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.forename: Filippo
authors.initials: F
authors.lastname: Bellati
authors.forename: Luca
authors.initials: L
authors.lastname: Pierelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Marianna
authors.initials: M
authors.lastname: Nuti
mesh_terms: D000117:Acetylglucosamine / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D018396:Mucin-1 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D037181:Lectins, C-Type; C506225:MGL lectin, human; C060192:MUC1 protein, human; D018396:Mucin-1; D016328:NF-kappa B; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium; D000117:Acetylglucosamine