title: Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells.
abstract: Dendritic cells (DCs) are APCs that play an essential role by bridging innate and adaptive immunity. DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is one of the major C-type lectins expressed on DCs and exhibits high affinity for nonsialylated Lewis (Le) glycans. Recently, we reported the characterization of oligosaccharide ligands expressed on SW1116, a typical human colorectal carcinoma recognized by mannan-binding protein, which is a serum C-type lectin and has similar carbohydrate-recognition specificities as DC-SIGN. These tumor-specific oligosaccharide ligands were shown to comprise clusters of tandem repeats of Lea/Leb epitopes. In this study, we show that DC-SIGN is involved in the interaction of DCs with SW1116 cells through the recognition of aberrantly glycosylated forms of Lea/Leb glycans on carcinoembryonic Ag (CEA) and CEA-related cell adhesion molecule 1 (CEACAM1). DC-SIGN ligands containing Lea/Leb glycans are also highly expressed on primary cancer colon epithelia but not on normal colon epithelia, and DC-SIGN is suggested to be involved in the association between DCs and colorectal cancer cells in situ by DC-SIGN recognizing these cancer-related Le glycan ligands. Furthermore, when monocyte-derived DCs (MoDCs) were cocultured with SW1116 cells, LPS-induced immunosuppressive cytokines such as IL-6 and IL-10 were increased. The effects were significantly suppressed by blocking Abs against DC-SIGN. Strikingly, LPS-induced MoDC maturation was inhibited by supernatants of cocultures with SW1116 cells. Our findings imply that colorectal carcinomas affecting DC function and differentiation through interactions between DC-SIGN and colorectal tumor-associated Le glycans may induce generalized failure of a host to mount an effective antitumor response.
authors.affiliation: Research Center for Glycobiotechnology, Department of Molecular Physiology, College of Information Science and Engineering, Ritsumeikan University, Shiga, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nonaka
authors.forename: Bruce Yong
authors.initials: BY
authors.lastname: Ma
authors.forename: Ryuuya
authors.initials: R
authors.lastname: Murai
authors.forename: Natsuko
authors.initials: N
authors.lastname: Nakamura
authors.forename: Makoto
authors.initials: M
authors.lastname: Baba
authors.forename: Nobuko
authors.initials: N
authors.lastname: Kawasaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Hodohara
authors.forename: Shinji
authors.initials: S
authors.lastname: Asano
authors.forename: Toshisuke
authors.initials: T
authors.lastname: Kawasaki
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D018395:CA-19-9 Antigen; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology*; D006028:Glycosphingolipids / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D007983:Lewis Blood Group Antigens; D008024:Ligands; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020298:U937 Cells; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D018395:CA-19-9 Antigen; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D006028:Glycosphingolipids; D037181:Lectins, C-Type; D007983:Lewis Blood Group Antigens; D008024:Ligands; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C069847:CD66 antigens; C476448:disialyl Lewis a antigen; C072748:trifucosyl-Lewis-b antigen