Fractalkine inhibition improves survival and reduces tumor immune cell infiltration in orthotopic murine glioma models

We sought to examine the effect of AZD8797-induced CX3CR1 inhibition on tumor macrophage infiltration and survival in a murine glioma model.We treated mice with AZD8797 and monitored them for the development of neurologic symptoms and survival.Survival was longer in the AZD8797-treated mice compared to that of control mice (41 vs 22 days, P = .005).We observed significant downregulation of CX3CR1 in AZD8797treated tumor specimens (P < .0001),accompanied by a significant decrease in macrophage infiltration and CCL2 levels.Thus, pharmacologic inhibition of CX3CR1 signaling with AZD8797 improved survival and attenuated immune infiltration in our murine glioma model.The CX3CR1/CX3CL1 signaling axis has been shown to be an important mediator of tumor behavior in glioma.A common CX3CR1 variant, V249I, is associated with decreased signaling activity and a lower number of CX3CL1 binding sites.This polymorphism has been shown to improve survival in patients with low-grade glioma (LGG) 1 and high-grade 2 glioma (HGG).Our group has shown that LGG patients with the V249I variant have reduced M2 macrophage infiltration, CCL2 presence, and microvessel density, 1 while others have shown that HGG patients with this variant also have reduced peritumoral microglial infiltration. 2Given these findings and their association with decreased CX3CR1 signaling, inhibition of the CX3CR1 axis represents a potential opportunity for novel anti-glioma therapy.We sought to investigate the effects of AZD8797, an allosteric, noncompetitive inhibitor of CX3CR1, on tumor immune cell infiltration and survival in orthotopic mouse models of glioblastoma. 3e obtained 4-to 8-week-old C57BL/6 mice in accordance with our institutional Animal Care and Use Committee.The right frontal lobes of mice were implanted with 5 10 4 mCherry-Luciferase labeled GL-261 cells.Mice were allocated in a sex-balanced fashion to the treatment arm injected intraperitoneally daily with 80 g/kg AZD 8797 dissolved in dimethyl sulfoxide (DMSO), as per the experimental protocol of Chen et al. 4 Mice in the control arm were injected intraperitoneally daily with phosphate-buffered solution