title: The interaction between Siglec-15 and tumor-associated sialyl-Tn antigen enhances TGF-β secretion from monocytes/macrophages through the DAP12-Syk pathway.
abstract: We previously demonstrated that Siglec-15, a member of the Siglec family of glycan-recognition proteins, is expressed on a subset of macrophages and preferentially recognizes the sialyl-Tn (sTn) antigen, a tumor-associated glycan structure. In this study, we report on the biological significance of the Siglec-15-mediated interaction between monocytes/macrophages and cancer cells. Siglec-15 is expressed on tumor-associated macrophages (TAMs) in various human tumor tissues. We further demonstrated that its expression is substantially elevated in macrophage colony-stimulating factor-induced M2-like macrophages, which produced more transforming growth factor-β (TGF-β) in response to sTn-positive cells than to negative cells. We designed a co-culture model of THP-1 (human monocytic leukemia) cells and H157 (human lung carcinoma) cells mimicking the interaction between monocytes/macrophages and cancer cells that recapitulated the enhanced TGF-β production in Siglec-15 expressing THP-1 cells by the cellular interaction with sTn expressing H157 cells. The enhanced TGF-β production required a direct interaction between the two cell lines through sialic acids. Siglec-15 associates with adaptor protein DNAX activation protein of 12 kDa (DAP12) at the binding determinant Lys(274) in the transmembrane domain and transduces a signal to spleen tyrosine kinase (Syk). The enhanced TGF-β secretion was significantly attenuated by Syk inhibitor treatment of THP-1 cells or by substitution of the Siglec-15 Lys(274) to Ala, which disrupts the molecular interaction between Siglec15 and DAP12. These findings indicate that Siglec-15 recognizes the tumoral sTn antigen and transduces a signal for enhanced TGF-β secretion in TAMs and further suggest that Siglec-15 on macrophages may contribute to tumor progression by the TGF-β-mediated modulation of intratumoral microenvironments.
authors.affiliation: Systems Glycobiology Research Group, RIKEN Advanced Science Institute, Wako, Saitama, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Takamiya
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ohtsubo
authors.forename: Shinji
authors.initials: S
authors.lastname: Takamatsu
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015295:Antigens, Tumor-Associated, Carbohydrate; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C527037:SIGLEC15 protein, human; C110546:TYROBP protein, human; D016212:Transforming Growth Factor beta; C055491:sialosyl-Tn antigen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase