American Association for Cancer Research
10780432ccr143118-sup-141585_1_supp_2878575_nk24l4.pptx (1.78 MB)

Supplemental Figure S5 from The Impact of Macrophage- and Microglia-Secreted TNFα on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment

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posted on 2023-03-31, 18:41 authored by W. Hans Meisen, Eric S. Wohleb, Alena Cristina Jaime-Ramirez, Chelsea Bolyard, Ji Young Yoo, Luke Russell, Jayson Hardcastle, Samuel Dubin, Kamaldeen Muili, Jianhua Yu, Michael Caligiuri, Jonathan Godbout, Balveen Kaur

Supplemental Figure S5. Murine TNFα reduces viral replication in infected human glioma cells.



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 TNFα-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFα on virus replication. TNFα blocking antibodies were used to evaluate the impact of TNFα 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 TNFα in response to infected glioma cells in vitro and in vivo. Using TNFα-blocking antibodies and macrophages derived from TNFα-knockout mice, we discovered TNFα-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors.Conclusions: The results of these studies suggest that FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy. Clin Cancer Res; 21(14); 3274–85. ©2015 AACR.