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* Research Center for Glycobiotechnology and
Department of Molecular Physiology, College of Information Science and Engineering, Ritsumeikan University, Shiga, Japan;
Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and
Division of Hematology, Shiga University of Medical Science, Shiga, Japan
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.
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1 This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas and Creative Research, A-14082203 (to T.K.), and for Scientific Research, C-18590471 (to B.Y.M.) from the Japan Society for the Promotion of Science, Ministry of Education, Culture, Sports, Science and Technology of Japan.
2 M.N. and B.Y.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Toshisuke Kawasaki and Dr. Bruce Yong Ma, Research Center for Glycobiotechnology, Ritsumeikan University, Shiga 525-8577, Japan. E-mail addresses: tkawasak{at}fc.ritsumei.ac.jp and byma{at}fc.ritsumei.ac.jp
4 Abbreviations used in this paper: DC, dendritic cell; CEA, carcinoembryonic antigen; CEAMA1, CEA-related cell adhesion molecule 1; CRD, carbohydrate recognition domain; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; h, human; Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; hIgG, human IgG; Le, Lewis; Lea, Galβ1–3(Fuc
1–4)GlcNAc; Leb, Fuc1–2Galβ1–3(Fuc1–4)GlcNAc; Lex, Galβ1–4(Fuc1–3)GlcNAc; Ley, Fuc1–2Galβ1–4(Fuc1–3)GlcNAc; Man, mannose; MBP, mannan-binding protein; MFI, mean fluorescence intensity; MoDC, monocyte-derived DC; pAb, polyclonal Ab; rhDC-SIGN, recombinant human DC-SIGN; U937-DC-SIGN, DC-SIGN-expressing U937 cell.
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