The Impact of Macrophage- and Microglia-Secreted TNFα on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment

Purpose: Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM. Experimental Design: Quantitative flow cytometry of mice with intracranial gliomas (+/- oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNF alpha-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNF alpha on virus replication. TNF alpha blocking antibodies were used to evaluate the impact of TNF alpha on oHSV therapy in vivo. Results: Flow-cytometry analysis revealed a 7.9-fold increase in macrophage infiltration after virus treatment. Tumor-infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNF alpha in response to infected glioma cells in vitro and in vivo. Using TNF alpha-blocking antibodies and macrophages derived from TNF alpha-knockout mice, we discovered TNF alpha-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNF alpha from the tumor microenvironment with TNF alpha-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors. Conclusions: The results of these studies suggest that FDA approved TNF alpha inhibitors may significantly improve the efficacy of oncolytic virus therapy. (C) 2015 AACR.