Modulating Hyaluronic Acid in Osteosarcoma using Genetically Engineered Mesenchymal Stromal Cells (GEMesys): effects on Macrophage metabolism and phenotype

Authors

• GE Forbes
• AT Browne
• RN Kaplan

Abstract

The tumor microenvironment (TME) of pediatric solid tumors involves a dynamic interplay of numerous alterations that create a tumor-supportive environment. One prominent change occurs in the extracellular matrix (ECM), where the ECM becomes denser and more rigid. Our research focuses on the accumulation of the ECM component hyaluronic acid (HA), whose increased deposition is linked to more aggressive cancers and impacts tumor immune response. We hypothesize that HA remodeling alters macrophage metabolism and resultant activity toward tumor-promoting behaviors. Since macrophages constitute a significant portion of sarcoma tumor volume, our study aims to investigate HA in osteosarcoma (OS) and its impact on macrophage activity. Utilizing immunofluorescent multiplex imaging (mIF) we identified a HA rich environment with abundant IBA1+ macrophages in OS TME. Following treatment with a novel cell therapy developed in our lab that targets and degrades HA in vivo, we observed a significant reduction of IBA1+ macrophage populations (P<0.01), by both flow cytometry and mIF. Furthermore, the immunosuppressive marker, PDL1 was reduced. Notably, 48 hours post-treatment, Arginase-1, a marker of anti-inflammatory macrophage metabolism, was increased. We hypothesize this is indicative of a shift in macrophage activity towards an anti-inflammatory, wound-healing phenotype, which is further suggested by the rebounding trend in collagen deposition. Our ongoing research includes a deeper investigation of the OS TME changes in response to HA degradation and their effects on macrophage metabolism.

Scientific Focus Area: Immunology

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