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Published on: April 3, 2018
Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells
Jakub Godlewski1,2, Mohamed Farhath1, Franz L Ricklefs1
1Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Oncolytic virus (OV) therapy shows promise for glioblastoma. Linking cancer cell secretomes to transcriptomes can predict patient response to OV treatment, improving outcomes.
Area of Science:
- Oncology
- Virology
- Immunology
- Proteomics
- Transcriptomics
Background:
- Oncolytic virus (OV) therapy is a promising glioblastoma treatment that targets cancer cells and stimulates immune responses.
- Patient sensitivity to OV therapy varies, necessitating predictive biomarkers.
- OV therapy functions as an anti-tumor vaccine by inducing immunogenic protein secretion from infected cancer cells.
Purpose of the Study:
- To establish a link between cancer cell transcriptome and secreted proteins (secretome) to predict OV therapy sensitivity in glioblastoma.
- To investigate the common molecular response of glioblastoma cells to OV infection.
- To correlate secretome profiles with patient survival outcomes.
Main Methods:
- Patient-derived glioblastoma cells were treated ex-vivo with herpes simplex virus type 1 (HSV1).
- Cellular transcriptome was analyzed using gene microarray.
- Secreted proteome was analyzed using mass spectrometry, with fractions separated into extracellular vesicles (EV) and EV-depleted components.
Main Results:
- Glioblastoma cells exhibited a unified transcriptomic response to OV infection, despite varied individual reactions.
- Upregulation of transcripts encoding secreted proteins indicated a common cellular response pathway.
- Co-secretion of proteins, regardless of EV or EV-depleted fraction, augmented the immune response and correlated with improved patient survival.
Conclusions:
- The OV-driven secretome is intrinsically linked to the anti-tumor immune response.
- Secretome analysis, integrated with transcriptome data, offers a predictive tool for OV therapy efficacy in glioblastoma.
- Targeting co-secreted proteins may enhance OV therapy outcomes and patient survival.
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