TMOD-26. CYTOMEGALOVIRUS PROMOTES GLIOBLASTOMA GROWTH VIA PDGF-D DRIVEN PERICYTE RECRUITMENT AND ANGIOGENESIS

Human cytomegalovirus (HCMV) is highly prevalent, and like other herpes viruses, can persist for life in its host in a latent state. However, HCMV can be severely pathogenic in immunocompromised individuals. Interestingly, HCMV proteins and nucleic acids have been identified in up to 90% of patients with the incurable brain tumor glioblastoma (GBM) as well as some other cancers. Accumulating data supports the clinical relevance of HCMV in GBM, with some encouraging responses reported with HCMV-targeted immunotherapies. Although various HCMV proteins increase cell proliferation and invasion, a mechanistic link between HCMV and cancer in vivo has not been established, and the role of HCMV in GBM remains a subject of debate. In the current report we show that perinatal murine CMV (MCMV) infection induces a pro-angiogenic secretome, increasing tumor growth, pericyte accumulation, angiogenesis and tumor blood flow in a murine GBM model. Specifically, we identify platelet-derived growth factor-d (PDGF-D) as a CMV-induced factor essential for tumor growth. In our model, MCMV can be seen in tumor cells and vascular pericytes, a finding that we confirm in human GBM specimens. The anti-viral drug cidofovir improves survival in MCMV-infected mice, inhibiting MCMV activation, PDGF-D expression, pericyte recruitment and tumor angiogenesis. Together these data provide the first mechanistic explanation of how CMV potentiates GBM growth in vivo, identify PDGF-D as a potential therapeutic target, and support the application of anti-viral approaches for GBM therapy.