ET-40 * ONCOLYTIC VIRUS INDUCED HMGB1 SECRETION AND ITS IMPACT ON TUMOR ANGIOGENESIS

Abstract

Glioblastoma multiforme (GBM) is a difficult-to-treat, and the most aggressive of primary brain tumors. Survival is less than 2 years despite aggressive therapy. Oncolytic virus (OV) therapy has shown tremendous benefits in the treatment of GBM and other tumors. This benefit is limited by host antiviral immune responses that enhance OV clearance and tumor progression. In this study, using both in-vivo and in-vitro models of GBM, we have tested the role of High mobility group box 1 (HMGB1) in OV therapy. HMGB1 is a nuclear protein that binds and regulates transcription factors. Extracellular HMGB1 functions as damage associated molecular pattern (DAMP), it mediates the inflammatory response upon binding to inflammation mediators, such as receptor of advanced glycated end product (RAGE), toll-like receptors (TLRs) 2, 4, and 9. Here, we report that; 1) HSV1716 infection induced significant secretion of HMGB1 in human glioma cell lines and glioma neurosphere cells alone or when co-cultured with microglia. 2) Measurement of HMGB1 in serum of mice with intracranial tumors revealed an increase in serum HMGB1 levels after virus treatment. 3) HSV1716 infection enhanced human brain microvascular endothelial cells (HBMEC) migration towards infected cells, which was blocked by HMGB1 blocking antibodies. 4) HMGB1 both directly enhanced HBMEC migration and induced production of VEGF by microglia cells co-cultured with glioma cells. 5) Pharmacologic inhibitor of HMGB1 (Garbexate (100uM)), and anti-HMGB1 polyclonal blocking antibody blocked HSV1716 induced HMGB1 secretion of VEGF in vitro and in vivo. Our findings suggest that OV therapy with HSV1716 activates proangiogenic pathway by induction of HMGB1, and that tumor microenvironment contributes to it proangiogenic property. Thus we conclude that OV therapy that target HMGB1 secretion and angiogenic axis may improve virotherapy of HSV1716, and other oncolytic herpes simplex virus in tumors.