Leveraging Zika virus driven myeloid cell responses to treat GBM

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Oncolytic viral therapy shows promise for high-grade solid tumors, but none have been shown to provide curative potential. This study explores the potential of harnessing the natural tropism of Zika virus (ZIKV) to target glioblastoma stem cells (GSCs) and reprogram the typically immune suppressive GBM tumor environment to an inflammatory, antigen-presenting environment that induces GBM-specific CD8+ T cell responses. The first goal of this proposal is to identify the cellular mechanisms that drive anti-tumor T cell responses following ZIKV treatment. Our research will examine the functional roles of two distinct myeloid cell subsets induced following ZIKV treatment - CCR2+ monocytes in the tumor microenvironment (TME) and dendritic cell subset-2 (DC-2s) in draining lymph nodes (dLN) - in driving anti-tumor T cell responses against GBM. Additionally, our study will examine the synergistic therapeutic potential of a highly novel Flt3 ligand therapy and ZIKV combination therapy as a strategy to activate both dendritic cell subset-1 (DC-1s) and DC-2, to maximize anti-tumor CD8+ T cell responses and subsequent GBM rejection. This research is significant because 1) it addresses the potential of ZIKV as an effective oncolytic virus for GBM treatment, 2) identifies key cellular mechanisms that contribute to its anti-tumor effects and 3) addresses the current failure of immunotherapy and maps a therapeutic path forward.