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: Rina Takamiya, Kazuaki Ohtsubo, Shinji Takamatsu, Naoyuki Taniguchi, Takashi Angata
• Journal: Glycobiology (Glycobiology) Vol. 23 Issue 2 Pg. 178-87 (Feb 2013) ISSN: 1460-2423 [Electronic] England
• PMID: 23035012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, Tumor-Associated, Carbohydrate
• Immunoglobulins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• SIGLEC15 protein, human
• TYROBP protein, human
• Transforming Growth Factor beta
• sialosyl-Tn antigen
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase

Topics

• Adaptor Proteins, Signal Transducing (immunology, metabolism)
• Antigens, Tumor-Associated, Carbohydrate (immunology, metabolism)
• Cell Line, Tumor
• Coculture Techniques
• Humans
• Immunoglobulins (immunology, metabolism)
• Intracellular Signaling Peptides and Proteins (immunology, metabolism)
• Macrophages (immunology, metabolism)
• Membrane Proteins (immunology, metabolism)
• Monocytes (immunology, metabolism)
• Protein Binding
• Protein-Tyrosine Kinases (immunology, metabolism)
• Signal Transduction
• Syk Kinase
• Transforming Growth Factor beta (metabolism)