Chen, Ashley2020-02-142021-02-142020-02-14http://hdl.handle.net/10393/40176http://dx.doi.org/10.20381/ruor-24410Tumour cells evade immune responses by multiple mechanisms in the tumour microenvironment, including through the expression of immunosuppressive molecules. The programmed cell death ligand 1 (PD-L1) plays a major role in this immunosuppression, and its expression is often up regulated as a result of innate and adaptive resistance mechanisms. Recent studies have discovered that the expression of PD-L1 can also extend to the nanoparticles that are naturally released by these cells, termed extracellular vesicles (EVs). Immune checkpoint inhibitors (ICIs) have shown great promise in blocking these immune-silencing interactions, but they remain hindered by their low response rates and toxic side effects. In addition, it has been found that the presentation of PD-L1 by EVs can be resistant to these established ICI therapies, further limiting their success. Here, we report a novel technique in which the oncolytic virus, Vaccinia virus, can be engineered to produce PDL1- targeting EVs as a form of immune checkpoint blockade. Our results show that our tailored EVs can target and neutralize immunosuppressive PD-L1, leading to enhanced anti-tumour immunity. Overall, this demonstrates the potential of using this technique to generate future EV-based immunotherapies.enCancerOncolytic VirusesExtracellular VesiclesImmunoresistanceImmunotherapiesThesis