Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells

SIMPLE SUMMARY: Proteins secreted by cancer cells in response to oncolytic virus anti-tumor therapy constitute the instructions for the immune cells. Yet as there are hundreds of proteins, including those encapsulated in vesicles, whose message drives the mobilization of immune cells, we aimed to decipher the instruction sent by cancer cells in response to therapy. Searching the cataloged vesicle and vesicle-free secreted proteins, we found that the proteins associated with the favorable survival of brain cancer patients were those that have the power to mobilize the immune cells. Thus, this approach established cancer-secreted contributors to the immune–therapeutic effect of the oncolytic virus. ABSTRACT: Oncolytic virus (OV) therapy, which is being tested in clinical trials for glioblastoma, targets cancer cells, while triggering immune cells. Yet OV sensitivity varies from patient to patient. As OV therapy is regarded as an anti-tumor vaccine, by making OV-infected cancer cells secrete immunogenic proteins, linking these proteins to transcriptome would provide a measuring tool to predict their sensitivity. A set of six patient-derived glioblastoma cells treated ex-vivo with herpes simplex virus type 1 (HSV1) modeled a clinical setting of OV infection. The cellular transcriptome and secreted proteome (separated into extracellular vesicles (EV) and EV-depleted fractions) were analyzed by gene microarray and mass-spectroscopy, respectively. Data validation and in silico analysis measured and correlated the secretome content with the response to infection and patient survival. Glioblastoma cells reacted to the OV infection in a seemingly dissimilar fashion, but their transcriptomes changed in the same direction. Therefore, the upregulation of transcripts encoding for secreted proteins implies a common thread in the response of cancer cells to infection. Indeed, the OV-driven secretome is linked to the immune response. While these proteins have distinct membership in either EV or EV-depleted fractions, it is their co-secretion that augments the immune response and associates with favorable patient outcomes.