High-grade glioma (HGG) is one of the deadliest childhood brain tumors. Despite our best effort, no treatment to date has improved survival of children with HGG. All these children die within 1-2 years of diagnosis. One critical reason that current anti-neoplastic therapies fail to provide a durable response is the adaptive nature of the tumor microenvironment. Understanding the immune microenvironment of pediatric HGG is paramount to developing immunotherapy-based trials, and predicting response to immunotherapy, but unfortunately this remains an unmet need. This proposal will provide the critical lacking information required for the design of future planned immunotherapeutic trials for this disease. Our preliminary data demonstrate that the most abundant non-neoplastic cells in pHGG microenvironment are immune cells called are tumor-associated macrophages (TAMs). Increased infiltration of TAMs is associated with decreased survival time of pHGG- bearing mice. The major goals of this proposal are to analyze the cellular composition, localization and molecular profiles of TAMs (bone marrow-derived vs. resident microglia), as well as to characterize the spatial and temporal dynamics of their infiltration in pHGG. Additionally, this proposal will use genetic and pharmacological approaches to target the IL-1?/IL1R1 signaling pathways, and determine their impact on tumor growth and TAM infiltration in pHGG. Characterizing the tumor cell-TAM relationship is a prerequisite for developing effective immunotherapies that leverage the intrinsic functions of the immunosuppressive innate immunity to allow T cells to effectively eliminate tumor cells.
): The grim prognosis and lack of therapeutic options for pediatric HGG highlights the urgency of not only developing new treatment modalities. Understanding the immune microenvironment of pediatric is paramount to developing immunotherapy-based trials, and predicting response to immunotherapy, but unfortunately this remains an unmet need. This proposal will provide the critical lacking information that is necessary for the design of future planned immunotherapeutic trials for these diseases.