Identifying gene expression signatures of oncolytic virus response in patient-derived pancreatic ductal adenocarcinoma organoids

Pancreatic ductal adenocarcinoma is among the deadliest cancers, with a poor prognosis. Viro-immunotherapy using oncolytic viruses represents a promising treatment. However, pancreatic ductal adenocarcinoma from different patients responds variably to these therapies, highlighting the need for predictive biomarkers. This study aimed to identify gene expression profiles that predict responses to oncolytic viruses. Patient-derived organoids (PDOs) from ten pancreatic ductal adenocarcinoma patients were evaluated for sensitivity to Newcastle disease virus (NDV), reovirus (RV), measles virus, and a gorilla-derived adenovirus. The sensitivity data revealed heterogeneous responses, with nine of ten PDOs being sensitive to at least one virus. The sensitivity of PDOs was correlated with their baseline transcriptome, resulting in gene expression profiles associated with sensitivity to each oncolytic virus. Gene Ontology analysis of the gene expression profiles revealed that intracellular aberrations, particularly those involved in embryonic development, were primary determinants of sensitivity. Additionally, for some oncolytic viruses (OVs), the gene expression profiles linked to sensitivity were associated with genes regulating cell cycle, metabolism, and cell proliferation. Screening tumors for these gene profiles may aid in selecting effective viral treatments for pancreatic ductal adenocarcinoma, providing the stepping stone toward personalized viro-immunotherapy.