Abstract 159: LYVE-1-expressing macrophages modulate the hyaluronan-containing extracellular matrix in the mammary stroma and contribute to mammary tumor growth

Abstract

Abstract Macrophages represent a heterogeneous myeloid population with diverse functions in normal tissues and tumors. While macrophages expressing the cell surface marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) have been identified in stromal regions of the normal mammary gland and in the peri-tumoral stroma, their functions within these regions are not well-understood. Using a genetic LYVE-1+ macrophage deletion mouse model, we demonstrate that loss of LYVE-1+ macrophages is associated with altered extracellular matrix remodeling in the normal mammary gland and reduced mammary tumor growth in vivo. In further studies focused on investigating the functions of LYVE-1+ macrophages in the tumor microenvironment, we demonstrate that LYVE-1 expression correlates with an increased ability of macrophages to bind, internalize, and degrade hyaluronan. Consistent with this, we show that deletion of LYVE-1+ macrophages correlates with increased hyaluronan accumulation in both the normal mammary gland and in mammary tumors. Analysis of single cell RNA sequencing of macrophages isolated from these tumors reveals that deletion of LYVE-1+ macrophages in tumors drives a shift in the majority of the remaining macrophages towards a pro-inflammatory phenotype, as well as an increase in CD8+ T cell infiltration. Together, these findings demonstrate that LYVE-1+ macrophages represent a tumor-promoting anti-inflammatory subset of macrophages that contributes to hyaluronan remodeling in the tumor microenvironment. Citation Format: Alexis K. Elfstrum, Annisa H. Rumahorbo, Braedan M. McCluskey, Kathryn L. Schwertfeger. LYVE-1-expressing macrophages modulate the hyaluronan-containing extracellular matrix in the mammary stroma and contribute to mammary tumor growth [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 159.