B7-H1 Expressing Macrophages Mediate Immunosupression in Glioma

The long-term goal of this proposal is to optimize immunotherapy for patients with malignant gliomas. Local immunoresistance and systemic immunosuppression represent major impediments to effective immunotherapy. The immune response to vaccination is largely dependent on tumor specific CD8+ cytolytic T cells (CTL), and can be suppressed by induction of CTL apoptosis. To date, we have demonstrated that tumor-associated macrophages (TAM) in glioma patients have upregulated expression of the surface protein B7-Homologue 1 (B7-H1). Also known as programmed death ligand 1 (PD-L1), B7-H1 is a surface ligand on tumor and immune cells that binds to the programmed death 1 (PD-1) receptor on CTLs and can induce anergy or apoptosis. Our data demonstrates that TAMs in gliomas are polarized to an anti-inflammatory (M2) phenotype, resulting in upregulated expression of B7-H1. Naïve monocytes exposed to soluble factors from gliomas upregulate B7-H1 at the cell surface and can induce apoptosis of activated CTLs, independent of glioma cells. This data suggests that macrophage-mediated suppression of the CTL response may be a primary factor in both the local and systemic immunoresistance seen in glioma patients. In the mentored phase of this study, we have demonstrated that 1) glioma-derived factors stimulate monocytes/macrophages to produce IL-10, 2) IL-10 is sufficient to activate B7-H1 expression in monocytes/macrophages, 3) B7-H1 expression correlates with autologous CTL apoptosis when glioma patient blood is studied in vitro, and 4) monocyte/macrophage B7-H1 expression correlates with survival in patients receiving immunotherapy. Based on these data, we continue to hypothesize that tumor-derived soluble factors from gliomas induce IL-10 production in tumor-associated macrophages, which activates B7-H1 expression through autocrine signaling and results in clinically significant local and systemic immunosuppression. In the independent phase of this study, the long-term goals remain unchanged but the project aims have been updated. Having partially determined the biologic mechanism behind macrophage/monocyte associated immunosuppression, we now focus on identifying the impact of inhibiting this mechanism on tumor growth and patient outcomes.