GLIOMA-14 ELUCIDATING THE CELL-CELL INTERACTIONS AND GEO-SPATIAL ORIENTATION OF M2 POLARIZED MACROPHAGES/MICROGLIA WITHIN GBM'S TME AND INVESTIGATING THEIR IMMUNOSUPPRESSIVE EFFECT ON DENDRITIC CELLS

Abstract

Abstract Glioblastoma (GBM) is an incredibly aggressive and prevalent primary CNS tumor with dismal survival outcomes. GBM’s intra-tumor heterogeneity and lack of anti-tumor immune cell infiltration have proved to be formidable challenges to developing effective therapies. To overcome these hurdles, it is vital that we garner a better understanding of the cell-cell interactions occurring within the tumor microenvironment (TME) in situ. Accounting for the complexity and the spatial orientation of the components within the TME may offer insight into the multitiered layers of immunosuppression capitalized on by GBM tumors, thus elucidating the factors responsible for poor response to therapy and uncovering potential therapeutic targets that may offer more favorable therapeutic results for immunotherapies. Current in vitro and in vivo models, however, sorely limit our ability to probe these distinct attributes while preserving the intricate nature of the TME. To bridge this gap, we have devised a novel organotypic brain slice culture (BSC) model using tumor-bearing C57BL/6J mice, allowing us to characterize the tumor milieu in situ. We have identified a large infiltration of macrophages and microglia polarized to the M2 anti-inflammatory phenotype within the TME. Leveraging this platform, we sought to define further the factors contributing to the dynamic impacts of GBM immunosuppression, such as the tolerogenic response in dendritic cells (DC) upon interaction with the TME. We have demonstrated outcomes similar to those seen in vivo following the introduction of DCs to tumor-bearing BSCs, further supporting the physiological relevancy of this model, and have since worked to unravel elements responsible for this response.