IMMU-02. Microglia Depletion Demonstrates a Time-dependent But Sex-independent Decrease in Survival in a Murine Model of Glioblastoma

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor. The tumor microenvironment (TME) has been implicated in the aggressiveness and resistance to chemotherapy. Myeloid cells, consisting of resident microglia and infiltrating macrophages, comprise the majority of the TME and engage in crosstalk with GBM cells, with GBM cells promoting a shift of these cells to an anti-inflammatory phenotype. These pro-tumor myeloid cells promote tumor cell invasion and proliferation and have been associated with decreased survival in humans. PLX3397, Pexidartinib, is a CSF1r inhibitor previously used in clinical trials that has shown efficacy in depleting microglia within the brain. Thus, while many studies have established the pro-tumor polarization of microglia in GBM, a timeline for this shift has not yet been established. Syngeneic GBM models (SB28) were implanted into 6–12-week-old C57Bl/6 male and female mice. PLX3397 was used to deplete microglia, and three timepoints of depletion were investigated: -5, +5, and +10 days post-implantation. Mice were kept on PLX3397 or control chow until neurologic endpoint was reached. Microglia depletion 5 days before implantation of GBM cells decreased survival in both males and females (p<0.001) in a sex-independent manner (median survival 13 versus 19 days). Microglia depletion beginning at 5 days post-implantation also resulted in a decreased survival (p = 0.03), however, at a decreased magnitude (median survival 16 versus 17.5 days). Microglia depletion at 10 days after implantation demonstrated increased survival (p=0.047) compared to control mice (median 16 versus 13 days). Microglia depletion with PLX3397 demonstrates a temporal effect on survival in a murine model of GBM. These results demonstrate the potential time-dependent role of microglia in the acute phase of GBM implantation and provide insight into the evolving phenotype across time.