IB-10 * A DUALITY OF ROLES FOR PERFORIN IN CD8+ T CELL- GLIOMA INTERACTIONS: CONTRIBUTIONS TO CYTOTOXICITY AND ALTERED VASCULAR PERMEABILITY

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive malignancy of the central nervous system that exhibits extensive vascularization and a high degree of invasiveness into the surrounding brain parenchyma. Recent evidence in both animal model systems and clinical trials have demonstrated the viability of immunotherapeutic strategies at selectively targeting tumor cells, with the generation of tumor antigen-specific CD8+ T cells strongly correlating to reductions in tumor burden. We have utilized the GL261 glioma model in immune-competent C57BL/6 mice to demonstrate the efficacy of a novel picornavirus vaccination approach. Treatment of established gliomas with a picornavirus engineered to express tumor-specific antigens delayed tumor progression and extended survival, outcomes which were accompanied by increased tumor-specific CD8+ T cell responses in the brain. Importantly, both intracranial and peripheral vaccination routes were effective at promoting anti-tumor CD8+ T cell responses. Perforin, an immune effector molecule, is well characterized for its role in CD8+ T cell-mediated cytotoxicity. Our data demonstrate that, in addition to this role in direct tumor cell lysis, perforin also contributes to alterations in tumor vascular permeability. Untreated perforin deficient mice bearing GL261 gliomas demonstrated no difference in tumor burden compared to C57BL/6 controls. However, the heterogeneity of tumor vascular permeability in mice lacking perforin was significantly reduced. As such, we propose that perforin serves dual functions in CD8+ T cell-glioma interactions, contributing to both direct killing of tumor cells and immune-mediated alterations to tumor vasculature.