Tumour pericyte infections potentiate anticancer immunity after viral therapy

Abstract

The connection between virus infection and tumour regression dates to the 1800s, however, it wasn’t until recently that scientific advancements made it possible to explore the therapeutic mechanisms, resulting in their current clinical use as cancer therapies. Certain viruses selectively infect and kill tumour cells (oncolytic viruses (OVs)) resulting in tumour regression. However, current evidence suggests tumour cell infection is only part of a more complex therapeutic mechanism as regression is dependent on the immune system. This opened additional avenues of mechanistic research our lab was uniquely equipped to explore using intravital microscopy (IVM); a technique that facilitates visualization of virus infection and resulting immune responses in live mouse tumours in real time. Using IVM, we observed that infection in many tumours was primarily localized to non-tumour cells surrounding tumour vessels, which we determined to be pericytes through colocalization with common pericyte markers (NG2/PDGFRb). To investigate the unique contribution of pericyte infection to OV therapy, we developed a mouse model (LDLR-/-LRPAP1-/-; DKO) to significantly reduce tumour pericyte infection. When compared to wild type mice, DKO mice showed attenuated tumour responses to VSV treatment, suggesting a role for pericyte infection in the generation of anti-tumour immune responses by VSV. When human primary pericyte cultures were assessed, an increase in the production of T cell recruiting factors was observed following infection with VSV, which parallels the enhanced production of these same factors in tumour interstitial fluid from VSV infected mice. Recruitment of transferred T cells is increased in wild type tumours that support pericyte infection by VSV. However, DKO mice also showed enhanced T cell recruitment in response to VSV, despite reductions in pericyte infection. Therefore, further investigation is required to determine the mechanism of pericyte infection OV mediated tumour clearance. Overall, the data from this thesis suggests infection in the tumour following systemic virus therapy is primarily in pericytes, which enhance the VSV mediated anti-tumour immune response through modifying the tumour microenvironment, augmenting T cell mediated tumour clearance.