TMIC-18. CYTOMEGALOVIRUS ONCOMODULATION OF THE GLIOBLASTOMA TUMOR MICROENVIRONMENT: A ROLE FOR THE VIRAL-ENCODED GPCR, US28

Abstract

Abstract Glioblastoma (GBM) is a prevalent, malignant glioma, and patient prognosis is poor. Even with surgery and aggressive treatment, survival is a dismal 12-15 months. GBM therapeutic resistance is common, often resulting in tumor recurrence, due in part to cancer stem cells (CSCs) that are resistant to chemo- and radio-therapies. This highlights the need for novel treatments, which requires a deeper understanding of the GBM tumor environment. While controversial, emerging data implicate human cytomegalovirus (CMV) in GBM progression, including findings that CMV drives GBM cell proliferation. Our work confirms CMV accelerates GBM cell proliferation in vitro using patient-derived xenograft (PDX) GBM models. Intracranial injection of these infected cells into murine models also results in decreased survival relative to mock-infected cells, suggesting CMV infection influences survival in vivo. Further, we found the CMV-encoded G-protein coupled receptor (GPCR), US28, influences this, as infection of PDX-derived GBM cells in vitro with US28-deletion virus impacts cell proliferation. In murine models, we find wild type infected PDX-derived GBM cells result in a significant decrease in survival compared to mice receiving cells infected with CMV lacking US28, suggesting US28 expression confers improved overall survival in vivo. Additionally, we find expression of US28 is associated with significantly increased survival for female mice, whereas there was no statistical difference between male mice that received CMV-infected or uninfected GBM cells. This indicates CMV infection, and more specifically, US28 expression, adversely impacts survival of female mice. Collectively, our data further illuminate means by which CMV influences the GBM tumor microenvironment and survival. We are currently working to understand: 1) the impact of US28-mediated signaling pathways on the tumor microenvironment; and 2) the influence of US28 interacting partners on GBM progression, including EphA2, a receptor tyrosine kinase whose increased expression in GBM confers increased CSC invasiveness.