PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is the most common and the most lethal primary malignant brain tumor. Immuno- therapeutic strategies to promote an effective antitumor immune response hold great promise for GBM. Yet, significant barriers remain as the factors that regulate the glioma-associated immune response, including the microglia, macrophages, and T cells, are poorly defined. While GBM is broadly characterized by a lymphocyte- depleted, immunosuppressive phenotype, there is a growing appreciation for the diversity of glioma immune microenvironments. Data from our laboratory and others have identified RAF-driven glioma subtypes with distinct immune-enriched phenotypes, including increased CD8 T cells, microglia, and macrophages. By comparing immune-enriched and lymphocyte-depleted glioma subtypes, we have identified a novel role for the chemokine CXCL14 in promoting a tumor-specific effector CD8 T cell response. Secreted by tumor cells, CXCL14 promotes both T cell and macrophage chemotaxis. In this proposal, we investigate CXCL14 function in glioma and directly test its potential to counteract the immunosuppressive microenvironment of GBM. To do this we leverage our extensive collection of molecularly annotated human brain tumor samples, state-of-the-art technologies, and murine models for GBM that mimic the characteristic lymphocyte-depleted tumor microenvironment of human GBM.