Bozena Kaminska, Konrad Gabrusiewicz and Malgorzata Sielska
Recent clinical and experimental studies show an important role of tumor-infiltrating macrophages in tumor growth, metastasis and response to cancer treatments. Tumor-associated macrophages are attracted by tumor-released molecules which induce reprogramming/differentiation of macrophages/myeloid derived cells into anti-inflammatory cells known as alternatively activated, M2-type macrophages, in contrast to inflammatory M1-type. The stromal signals and components of immune microenvironment influencing glioma progression are poorly known and are likely distinct from those implicated in non-nervous system cancers. This review summarizes recent findings on characteristics of immune microenvironment of gliomas. Various functional properties of microglia in the normal and pathological central nervous system are now being revealed because of combinations of bone marrow transplantations and experimental disease models. Here, we describe some of the latest findings on the heterogeneity of glioblastoma-infiltrating brain macrophage, their alternative, immunosuppressive phenotype and contribution to glioma pathology. Recent attempts to determine a profile of cytokine/chemokine production and genes expression profiling on sorted CD11b+ cells from tumor tissues, revealed that many genes induced in M2-type macrophages from other tissues or in the context of helminth infections, are not up-regulated in CD11b+ cells isolated from gliomas. On the other hand, some genes characteristic for the alternative and pro-invasive phenotype: arg-1, mt1-mmp and cxcl14 were consistently activated in those cells. Furthermore, we discuss the potential for targeting interactions between glioma and brain macrophages in therapeutic interventions. Small molecule inhibitors of MAPK signaling with immunosuppressive properties, such as cyclosporine A and minocycline were shown to block infiltration and activation of microglia/macrophages in vitro, in organotypic brain slices and in vivo. Small molecule inhibitors with anti-inflammatory properties significantly reduced infiltration of brain macrophages, angiogenesis and tumor growth in mice, demonstrating that blockade of their proinvasive functions could be a novel therapeutic strategy in malignant gliomas.