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Abstract

In many cancers, including glioblastoma multiforme (GBM), the most aggressive primary brain tumor, immunosuppression is an important aspect of tumorigenesis that manifests as the accumulation of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). However, the underlying sequence of events driving Treg and MDSC recruitment in GBM remains unknown. Here, we demonstrate that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that recruits both CCR4+ Tregs and CCR2+Ly-6C+ monocytic MDSCs. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Furthermore, tumors grown in CCL2 knockout mice fail to maximally accrue Tregs and monocytic MDSCs. We demonstrate using mixed-bone marrow chimera assays that CCR4-deficient Tregs and CCR2-deficient monocytic MDSCs are defective in glioma accumulation. Finally, targeting this axis using a small molecule CCR4 antagonist significantly improved median survival. The significance of our findings is further corroborated by GBM patient data where high CCL2 gene expression is correlated with reduced overall survival. Furthermore, we observed that both macrophages and glial cells produce CCL2 in GBM patients. Collectively, we provide novel evidence supporting a paradigm in which glioma cells influence the microenvironment to recruit effectors of potent immunosuppression.

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