Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion

Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumours with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action – the inhibition of migration and invasion in paediatric brain tumours. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilising microtubules, inhibiting glycogen synthase kinase-3 and preventing localised clustering of adenomatous polyposis coli to the leading edge of cells. HSV1716 treatment also reduced tumour infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus to be used as a novel anti-invasive treatment strategy for paediatric brain tumours.