TMIC-113. An Alzheimer’s neuroinflammatory microenvironment resists glioblastoma immune hijacking

Abstract Glioblastoma (GBM) and Alzheimer’s disease (AD) are devastating, age associated disorders with no cure. Epidemiologic data has established an inverse comorbidity between AD and cancer, including GBM, with up to a 50% reduction of cancer incidence in AD patients. While the underlying biology remains unclear, myeloid cells, which are central players in both neurodegeneration and tumor immunity, may serve as a mechanistic link. We hypothesize that myeloid cells activated by pre-existing AD pathology suppress tumor growth more effectively than homeostatic microglia. In this study, age-matched APPNL-G-F/MAPT double knock-in (henceforth “AD”) and wildtype (WT) mice received orthotopic xenografts of syngeneic GBM cell lines (GL261, SB28) (n=15/sex/genotype). We observed a significant survival difference, with AD mice living an average of 20% longer than WT mice (p<0.0001). In vivo luciferase imaging revealed impaired engraftment of tumor cells in AD mice compared to WT a week post-engraftment (p<0.05). At the microscopic level, tumors in AD mice were found to have nearly 2-fold the amount of tumor-infiltrating myeloid cells (p<0.01), with the proportion of anti-tumoral “activated” myeloid cells also being greater (p<0.05). Tumors in AD mice were found to have markedly higher immune infiltrate at the tumor rim and margin (p<0.001). We also observed striking astrogliosis (GFAP+) and microgliosis (P2RY12+) in both the tumor rim (p<0.05) and margin (p<0.01) in AD animals. This robust glial response was significantly higher in AD mice bearing tumor compared to both WT mice bearing tumor and sham AD mice. Lastly, we utilized a luciferase stain to visualize tumor cells that invaded beyond the bulk tumor. We found that both the quantity (p<0.01) and invasion distance of tumor cells (p<0.05) was lower in AD mice. We demonstrate that an AD-induced inflammatory microenvironment antagonizes glioma growth, providing a foundation for novel GBM treatment strategies that potentially exploit these immune signals.