In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, contributing to tumor growth and maintaining a pro-tumor, immunosuppressed microenvironment. We have recently demonstrated that housing glioma-bearing mice in enriched environment (EE) reduced tumor growth, with effects mediated by BDNF and IL-15 (Garofalo et al., 2015). We now want to investigate whether housing glioma-bearing mice in EE reverts the immunosuppressive phenotype of invading myeloid cells. At this aim we will monitor myeloid cells for changes in their expression of inflammatory genes, in cell branching and in patrolling and phagocytic activity. We will also investigate whether the effects of EE are mediated by the interferon-(IFN)-gamma produced by NK cells, and by IL-15, a well known NK cell activator. These studies will be performed using a syngeneic mouse model of glioma, and will require the use of specific antibodies to deplete the NK cell population or the endogenous IFN-gamma, as well as the implantation of osmotic pumps for the controlled release of IL-15 or BDNF in the brain of glioma bearing mice, housed in the different conditions. BDNF+/- and IL-15ra-/- mice will be also used. At the end of the project, we will be able to describe the chain of molecular and cellular events involved in the modulation of myeloid cell phenotype eventually induced in glioma-bearing mice by the environmental changes.
