Abstract 1450: Tumor-associated glycans interact with macrophages through class-A scavenger receptor
Authors: Behjatolah Monzavi Karbassi, Thomas Kieber-Emmons, Steven R. Post
Journal: Cancer Research (2016)

Abstract Introduction. Tumor initiation and growth are associated with modifications to the glycan structure of glycoproteins, glycolipids and proteoglycans present on the cell surface. Suppression of the anti-tumor immune response is a putative mechanism linking tumor-associated-glycans to tumor progression. Within a tumor microenvironment, the conversion of macrophages from an activated, immunological type (referred to as M1) to an alternatively activated, IL-10 secreting type (referred to as M2) suppresses the immune response and potentiates tumor progression. We previously reported that the class A scavenger receptor (SR-A)-mediated macrophage activation enhances production of IL-10, indicating promotion of an immunosuppressive M2 phenotype. Therefore, tumor glycans may suppress immune responses by interacting with macrophages and promoting an M2 phenotype. Such interactions are most likely mediated by pattern recognition receptors such as SR-A. In the current study, we investigated whether tumor glycans interact with macrophages via binding to SRA. Methods. Binding of recombinant soluble SR-A to breast cancer cells and relevant glycan structures was assayed by flow cytometry and ELISA assays. N-glycosylation was inhibited by incubating cells with tunicamycin. Peritoneal macrophages were harvested from wild type (SR-A+/+) and knock-out (SR-A-/-) mice and used for ligand competition and functional assays. A peptide mimic of GlcNAc/GalNAc-containing tumor-associated carbohydrates was used for binding and competition assays. Results. To determine whether carbohydrates present on tumor cells are SR-A ligands, we examined the binding of a soluble SR-A protein to tumor cells. We found that soluble SR-A bound to breast cancer cells but not to normal epithelial cells, and that this tumor-specific binding of soluble SR-A was abolished by treating cells with tunicamycin. These results demonstrate that cell surface tumor-associated glycans are ligands for SR-A. Using purified glycans, we found that soluble SR-A bound to multiple breast cancer-associated glycans. To assess the potential consequence of glycan binding to SR-A on macrophage function, we adhered primary macrophages to plates coated with a carbohydrate-mimetic peptide and found that SR-A+/+ macrophages bound to CMP-coated plates showed increased IL-10 production relative to SR-A-/- macrophages. The CMP also competed for acetylated LDL binding to macrophages, indicating that it is a ligand for SR-A. These results suggest that SR-A binding to carbohydrate promotes macrophages to adopt an M2 phenotype. Conclusions. Together, our results indicate that tumor-associated glycans interact with macrophages via SR-A, and that this interaction leads to production of IL-10, which is a key characteristic of immunosuppressive (M2-like) macrophages. Citation Format: Behjatolah Monzavi Karbassi, Thomas Kieber-Emmons, Steven R. Post. Tumor-associated glycans interact with macrophages through class-A scavenger receptor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1450.