Dissecting the interplay between the endogenous immune response and oncolytic virus therapy in pediatric brain tumors
NEURO-ONCOLOGY(2023)
Abstract
Abstract Oncolytic virus (OV) elicits an antitumor immune response in addition to tumor-cell killing. However, it is unknown if a pre-existing antitumor immune response aids or hinders OV therapy. To study the interplay between the endogenous immune response and OV we profiled tumors from immunocompetent intracranial models of medulloblastoma and glioblastoma treated with measles virus (MV) and retrovirus (Toca-511), using single-cell and bulk-RNA sequencing. For both models, we assayed specimens from two treatment groups, a mid-treatment group where mice were sacrificed upon observation of treatment response, and a post-treatment group where treatment-resistant mice were sacrificed when they had succumbed to their disease. As controls, we included a cohort treated with heat-inactivated virus and a cohort treated with PBS. Both MV and Toca-511 OV therapies significantly improve survival compared to controls. From each of the MV and Toca-511 treatment/control groups, 3 mice per group were profiled via RNA sequencing. Additionally, tumors from 5 mice treated with MV alone and 4 mice treated with MV and anti-PD1 immune-checkpoint blockade (ICB) were subjected to single-cell RNA sequencing (scRNA-seq). ScRNA-seq generated 38,491 cells after filtering for quality control and successfully captured both endogenous and viral RNAs. We found that in samples treated with both OV and ICB there were higher rates of virally infected cells, depletion of M2-polarized myeloid infiltrates, and depletion of endothelial cells, compared to controls. Comparing virally infected tumor cells to non-infected controls we observed a down-regulation of translation initiation-complex genes and an upregulation of markers of oxidative phosphorylation. Infected cells from treatment-resistant tumors upregulate antigen presentation and myeloid chemotaxis genes. These studies show that OV enhances survival and anti-brain-tumor immunity. They support MV and ICB as potentially being synergistic. They suggest translation control and perturbation of the myeloid compartment as strategies for enhancing intracellular MV proliferation and infection efficiency, respectively.
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Key words
oncolytic virus therapy,immune response,endogenous immune response,tumors
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