Oncolytic viruses in malignant pleural mesothelioma
File(s)
Author(s)
Ladhar, Pamelbir
Type
Thesis
Abstract
Mesothelioma is an aggressive cancer of the serosal membranes with a median survival of 9 to 12 months. Oncolytic viruses are a next-generation therapy. The viruses directly lyse cancer cells and prime the immune system. Interferon locus deletions in mesothelioma samples could render them susceptible to oncolytic viruses.
This PhD project aimed to investigate the hypothesis that oncolytic viruses exert beneficial anti-tumour effects on mesothelioma cells. Three oncolytic viruses (Reovirus, Herpes Simplex virus 1716 and Maraba virus) were first investigated using two commercial mesothelioma cell lines (MSTO-211H and H2052). Viability assays indicated superior killing of mesothelioma cells by Maraba compared to the other two viruses. Subsequently, the Superior Killing Virus (SKV) became available and comparator experiments, using eight patient-derived primary mesothelioma cell lines (PMCs), revealed SKV to be superior to Maraba. Notably interferon deletions did not appear to affect mesothelioma cells’ responses to either Maraba or SKV.
A genome wide transcriptomics time series experiment was performed using SKV and three PMCs of varying interferon locus deletion status, with RNA sequencing data undergoing maSigPro analysis to assess host transcriptional responses over time. Similar expression signatures were seen for the three lines including signatures related to increased transcription of histones and cytoskeletal changes. Importantly an overall antiviral response appeared absent. Examination of the SKV genome RNA sequencing data revealed viral genes, such as F17R and E3L, that may modulate the host response and inhibit an antiviral response.
The results have shown that oncolytic viruses have the potential to be used in mesothelioma treatment. SKV demonstrated superiority to the three other oncolytic viruses investigated, with utility irrespective of the IFN locus status of the mesothelioma cell line. The global transcriptomics data provided important insights into the host response to SKV infection and relevant SKV proteins which could assist in improved oncolytic virus design.
This PhD project aimed to investigate the hypothesis that oncolytic viruses exert beneficial anti-tumour effects on mesothelioma cells. Three oncolytic viruses (Reovirus, Herpes Simplex virus 1716 and Maraba virus) were first investigated using two commercial mesothelioma cell lines (MSTO-211H and H2052). Viability assays indicated superior killing of mesothelioma cells by Maraba compared to the other two viruses. Subsequently, the Superior Killing Virus (SKV) became available and comparator experiments, using eight patient-derived primary mesothelioma cell lines (PMCs), revealed SKV to be superior to Maraba. Notably interferon deletions did not appear to affect mesothelioma cells’ responses to either Maraba or SKV.
A genome wide transcriptomics time series experiment was performed using SKV and three PMCs of varying interferon locus deletion status, with RNA sequencing data undergoing maSigPro analysis to assess host transcriptional responses over time. Similar expression signatures were seen for the three lines including signatures related to increased transcription of histones and cytoskeletal changes. Importantly an overall antiviral response appeared absent. Examination of the SKV genome RNA sequencing data revealed viral genes, such as F17R and E3L, that may modulate the host response and inhibit an antiviral response.
The results have shown that oncolytic viruses have the potential to be used in mesothelioma treatment. SKV demonstrated superiority to the three other oncolytic viruses investigated, with utility irrespective of the IFN locus status of the mesothelioma cell line. The global transcriptomics data provided important insights into the host response to SKV infection and relevant SKV proteins which could assist in improved oncolytic virus design.
Version
Open Access
Date Issued
2022-03
Date Awarded
2022-11
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Cookson, William
Moffatt, Miriam
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)