IMPS-12CCR2 DEFICIENCY REDUCES THE INFLUX OF CD11b+ MACROPHAGES IN MURINE GLIOMAS

Abstract

INTRODUCTION: Glioblastomas (GBMs) are characterized by behavioral aggressiveness and a dismal prognosis despite multimodality therapies. While high numbers of microglia/macrophages are found within GBM, little is known of their specific function within this microenvironment. Mounting evidence indicates a role for these cells in tumor progression and therapy resistance. Microglia/macrophages can constitute as high as 30% of total cells within GBM and there is evidence for the positive correlation between numbers of infiltrating microglia/macrophages and tumor proliferation rate. Sources of these mononuclear cells include brain parenchyma (microglia) and bone marrow (BM). Despite the potential significance of GBM-associated microglia/macrophages to tumor progression and decreased therapeutic efficacy, the mechanisms by which these cells infiltrate GBM are unknown. This localization likely requires the presence of chemokines within the tumor microenvironment and their cognate receptors expressed on microglia/macrophages. While brain-derived microglia and BM-derived macrophages share similar characteristics they also likely exert distinct functions within, and utilize unique mechanisms to gain access to, the GBM microenvironment. It is reported that peripheral BM-derived proinflammatory mononuclear cells express the chemokine receptor CCR2 and traffic into inflamed tissues, including irradiated adult brain, in a CCR2-dependentmanner.OBJECTIVE: Understand the role ofCCR2in macrophage function within GBM, with the long term goal of inhibiting the protumor promoting activities of these cells. METHODS: We performed immunohistochemical analyses of human GBM sections and analyzed the presence of CCR2+CD11b+ macrophages in CCR2-sufficient and -deficient GL261- and KR158-glioma bearing mice. RESULTS: GBM-associated CD68+ macrophages express CCR2. Prominent numbers of CCR2+CD11b+ macrophages were found within murine GL261 and KR158 gliomas that were distinct from CX3CR1+CD11b+ cells. The tumor localization of the former cells was greatly reduced in CCR2-deficient mice. CONCLUSION: Blocking CCR2 could impact the presence of GBM-associated macrophages, which may in turn decrease tumor growth and/or augment the efficacy of current treatments.