Role of CX3CR1 Signaling in Malignant Transformation of Gliomas.

BACKGROUND: Chemokine signaling may contribute to progression of low grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3CR1 signaling in malignant transformation of LGGs. METHODS: Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype dependent alterations in survival, gene expression, and tumor microenvironment. A genetically-engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. RESULTS: LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 versus 9.8 years, P < 0.05) and progression-free survival (8.6 versus 6.5 years, P < 0.05) compared to those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, co-expression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. CONCLUSIONS: CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.