Metabolic Control of Immune Suppression in Gliomas

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 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer. Even after surgical resection, irradiation and chemotherapy, the median survival for patients with GBM remains at only 14.6 months, with 26% of patients alive after 2 years. The potent immunosuppression induced by GBM is one of the primary obstacles to finding effective immunotherapies. This immunosuppression is associated with a significant accumulation of regulatory T cells (CD4+CD25+FoxP3+, Tregs) within the tumor microenvironment and is considered to be one of the primary obstacles inhibiting the tumor rejection functions of CD8+ cytotoxic T cells. It is therefore important that future immunotherapies simultaneously arm effector CD8+ cytotoxic T cells, while at the same time inhibiting immunosuppressive mechanisms. Building on our expertise in brain tumor immunology, we now propose to elucidate the mechanisms involved in GBM immunosuppression and to investigate the function of a novel immunomodulatory agent in the context of a phase I/II human clinical trial. Cumulatively, our studies will comprehensively characterize the immunosuppressive microenvironment of gliomas and test the clinical efficacy of a new drug capable of reversing GBM mediated immune tolerance.