Abstract 186: Tumor exosome-macrophage interactions: The role of tumor-associated glycans and scavenger receptor class A

Abstract

Abstract Introduction: Increased macrophage infiltration and polarization towards a breast tumor-supportive phenotype have been linked to therapy resistance, immune suppression, and poor patient prognosis. Despite their importance, the specific interactions that drive tumor-associated macrophage (TAM) polarization remain poorly understood. The class A scavenger receptor (SR-A) is a pattern-recognition receptor expressed by macrophages, and the accumulation of SR-A-expressing TAMs has been correlated with poor patient outcomes. Our preliminary data show that SR-A binds to tumor-associated glycans (TAGs) on the surface of breast cancer cells. However, how macrophages bind tumor cell ligands in the tumor microenvironment (TME) is not clear. Tumor-derived exosomes (TDEs) are secreted extracellular vesicles that resemble the tumor cell membrane, carrying cargo that may mediate an immune response within the TME. In this study, we investigated whether TDE glycans represent tumor cell-surface TAGs and whether TDEs interact with macrophages through SR-A. Methods: TDEs were isolated from the murine breast cancer cell line (E0771) by ultracentrifugation of the cell culture medium and then sized and counted using nanoparticle tracking analysis and electron microscopy. The glycans present on the tumor cell surface and TDEs were characterized using plant lectins in flow cytometry and sandwich ELISAs. The isolated TDEs were then fluorescently labeled, and their binding to the murine macrophage cell line Raw 264.7 was assayed by flow cytometry and fluorescence microscopy. Results: SR-A binds strongly to breast cancer cell lines, and a significant portion of the binding depends on the presence of cell surface N-linked glycans. Lectins reactive with sialylated and fucosylated terminal structures showed differential binding to tumor cells and TDEs. We observed that the glycan profiles of E0771 cells and exosomes isolated from E0771 cultures were similar. Our results indicate that TDEs interact with Raw 264.7 cells, and the interaction is mediated by SR-A. Conclusions: TDEs released in the TME can potentially interact with TAMs through SR-A. The glycan profile of TDEs is representative of host cells and may contribute to SR-A-mediated interaction with TAMs. Citation Format: Fariba Jousheghany, Emily S. Blitz, Samir V. Jenkins, Steven R. Post, Vinay Raj, Rajshekar A. Kore, Azemat Jamshidi-Parsian, Robert J. Griffin, Thomas J. Kelly, Behjatolah Monzavi-Karbassi. Tumor exosome-macrophage interactions: The role of tumor-associated glycans and scavenger receptor class A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 186.