Investigating the Role of Virus-Mediated Tumour Modulation in T Cell Centric Cancer Immunotherapy

Abstract

Cancer immunotherapy continues to be at the forefront of cancer treatment modalities delivering unprecedented outcomes. In this thesis we have investigated the combination of Oncolytic Viral Vaccines (OVVs) and Adoptive T Cell Therapy (ACT) for treating solid tumours. We used animal models, flow cytometry and high throughput transcriptomic analyses to characterize the therapeutic outcomes of such combination and understand the mechanisms behind its success on cellular and molecular levels. We focused on comparing the behaviour of different viruses, Vesicular Stomatitis Virus (VSV), and Vaccinia Virus (VacV), and showed that the choice of viral backbone indeed shapes the therapy outcome. While both viruses can achieve complete tumour regression when combined with ACT, VSV-treated tumours relapse shortly after remission. Additionally, we studied the effect of the virus route of administration and observed that intratumoural (IT) delivery leads to better overall survival of mice compared to intravenous (IV) delivery regardless of the viral backbone. Furthermore, we evaluated the necessity of virus replication in different tumour models. Our results show that virus replication, despite being dispensable for immunogenic tumour models, is necessary for durable outcomes in immunosuppressive models. Importantly, the reprogramming of the tumour microenvironment (TME) by OVVs was shown to be crucial for therapy success. Specifically, we show that unlike VSV, VacV is able to induce more inflammatory pathways, block metabolic pathways, cell cycle pathways and DNA repair pathways. We highlighted the role of inhibiting DNA repair pathways in preventing antigen loss and immune escape. Lastly, we examined the effect of the transcriptomic signature induced by VacV on the prognosis and survival of Skin Cutaneous Melanoma (SKCM) patients using a public dataset derived from the Cancer Genome Atlas (TCGA). Our analysis demonstrates that VacV transcriptomic signature correlates with favorable disease prognosis and better overall patient survival. In conclusion, the research described in this thesis reveals important insights pertaining to the choice of viral backbone, route of administration and unveils additional mechanisms by which OVVs complement the CD8+ T cell mediated elimination of tumour cells.