Understanding the Role of Pancreatic Ductal Adenocarcinoma Chemoresistance and Intertumoral Heterogeneity on Vesicular Stomatitis Virus-Based Oncolytic Therapy

摘要

Viruses are obligate intracellular parasites that are now being increasingly harnessed as therapeutics for human diseases. Investigating different cellular factors and processes that affect viral infection allows us to improve the efficacy of virus-based therapeutics. This dissertation examines a member of the order Mononegavirales, vesicular stomatitis virus (VSV), and is focused on 1) how chemoresistant pancreatic ductal adenocarcinoma (PDAC) impacts the efficacy of VSV-based oncolytic virotherapy and 2) how intertumoral heterogeneity of mouse PDACs impacts VSV-based oncolytic virotherapy and how intertumoral heterogeneity can be addressed in a PDAC mouse model. Here, for the first time, we examined how experimentally acquired chemoresistance impacts the effectiveness of OV therapy. We demonstrate that long-term exposure of PDAC cells to gemcitabine results in the development of cross-resistance of PDAC cells to gemcitabine and VSV. The increase in resistance to VSV correlated with upregulated levels of a subset of antiviral interferon related genes ISGs in gemcitabine resistant cell lines. First the first time, we also systematically examined the impact of intertumoral heterogeneity on oncolytic virus (OV) virus efficacy. We examined phenotypically and genotypically 3 commonly used allograftable mouse PDAC cell lines. Mouse PDAC cell lines showed high divergence in their permissiveness to VSV, which negatively correlated with their abilities to mount antiviral immune responses. Also, mouse PDAC showed high divergence in their karyotype and exome.