The long-term goal of this proposal is to optimize immunotherapy for patients with malignant glioma. Several trials have shown the feasibility and safety of glioma vaccines, however evidence of glioma immunotherapy efficacy is mostly lacking. Cancer immunoresistance and systemic immunosuppression represent major impediments to effective immunotherapy. Vaccine therapies designed to provoke a cellular immune response depend upon tumor specific CD8+ T cells. Tumor-specific cytolytic CD8+ T cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas. (B7-H1), also known as programmed death ligand 1 (PD-1), is a recently discovered cell surface protein that inhibits anti-tumor immunity by inducing CD8+ T cell apoptosis, impairing cytokine production, and diminishing the cytotoxicity of activated T cells. In glioma and other cancers, B7-H1 expression has also been associated with local expansion of CD4+ immunosuppressive T cells (Tregs) and apoptosis of CD4+ helper T cells (Thelp). In the present proposal, we endeavor to more directly study the effects of B7-H1 using an immunocompetent animal model. The GL261/ C57Blk model has all the necessary components for testing the importance of B7-H1 expression by intracranial tumor including: 1) a full repertoire of immune effector cells that can circulate throughout the brain and infiltrate tumor, 2) a glioma that robustly expresses B7-H1, 3) a glioma that can be genetically manipulated to decrease expression of B7-H1, 4) an animal host that can be treated with antibodies against B7-H1 or its receptor PD-1 to decrease B7-H1 mediated effects, and 5) a glioma that is immunogenic with known glioma associated antigens that can be targeted with vaccination using specific peptides such as GARC-177-85 and EphA2671-679. We will determine if B7-H1 expression by GL261 tumor cells induces local immunoresistance that affects tumor growth, immunologic tumor microenvironment, and response to vaccine therapy.
Although immunotherapy is among many novel therapeutic approaches for glioblastoma (GBM), efficacy has been precluded by local immunoresistance mediated by proteins such as B7 homolog 1 (B7-H1). Research proposed here will attempt to better understand the mechanism of B7-H1-mediated immunoresistance in GBM, which may provide important adjuvant therapies to boost the efficacy of immunotherapies and extend survival for patients with GBM.
