Deciphering the Glycan and Protein Interactome of Siglec-15: Unraveling its Role in Tumor-Associated Immunosuppression 2949

Abstract Description Immunotherapy has revolutionized cancer treatment, driving interest in strategies to counteract immune suppression within the tumor microenvironment. Siglec-15, a member of the sialic acid-binding immunoglobulin-like lectin family, has emerged as a key immunosuppressive molecule expressed by tumor-associated macrophages (TAMs), where it dampens T-cell responses. Despite its importance, the mechanisms underlying Siglec-15-mediated immunosuppression remain poorly understood. While the sialyl Tn (sTn) antigen—a truncated glycan structure overexpressed in many epithelial malignancies—has been identified as a ligand for Siglec-15, we observed that Siglec-15 binds to a variety of tumor cell types lacking sTn expression, suggesting the existence of additional ligands. In this study, we identified cell type-specific interactions between Siglec-15 and various glycoproteins, highlighting a complex glycan and protein interactome. Additionally, our findings implicate the sialyltransferase ST3Gal4 in generating glycan structures critical for Siglec-15 binding. These insights lay the groundwork for further investigation into the role of Siglec-15-expressing TAMs in suppressing T-cell responses. Future studies will focus on elucidating the mechanisms driving Siglec-15-mediated immunosuppression and developing strategies to disrupt this glyco-immune axis, with the goal of restoring effective anti-tumor immunity. Funding Sources Pharmacology T32 Training Grant- T32GM008076 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)