Abstract
Abstract Glioblastoma (GBM) is the most common brain malignancy in adults and has a dismal prognosis. Advances in standard-of-care treatments for GBM have not kept pace with those for other malignancies, in part due to the inefficacy of immunotherapies in treating GBM. The tumor microenvironment (TME) of GBM is heavily populated with pro-tumorigenic tumor-associated macrophages (TAMs) and lacks robust infiltration of T cells. Given that the number of TAMs in the TME correlates with poor prognosis, understanding the mechanisms by which they thrive is essential for discovering new therapies. Bulk RNASeq data from mouse tumors indicates that the fructose transporter, SLC2A5, is highly expressed on TAMs relative to peripheral myeloid cells. Furthermore, human glioblastoma single cell RNASeq (scRNASeq) data indicates that SLC2A5 is expressed specifically on microglia, the tissue resident macrophage of the brain. To assess the necessity of SLC2A5 in microglia, we orthotopically implanted CT2A or QPP4 glioblastoma cells into wild-type mice and mice lacking SLC2A5 (SLC2A5 KO mice). We observed a significant increase in median survival in SLC2A5 KO mice compared to wild-type mice. This indicates a necessity of fructose metabolism in microglia to promote tumorigenesis. Upon ex vivo analysis of the immune compartment of the TME, we observed that microglial cells from tumors in SLC2A5 KO mice have higher expression of MHC-II and PDL1 molecules on the cell surface compared to those from wild-type mice. Additionally, the CD4:CD8 T cell ratio in tumors from SLC2A5 KO mice was lower than that in tumors from wild-type mice. These data suggest that fructose metabolism in microglia facilitates an immunosuppressive phenotype that promotes GBM progression.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.