The role of cancer and non-cancer cell infections in systemic VSV∆M51 therapy

Abstract

Oncolytic viruses (OVs) such as Vesicular stomatitis virus (VSV∆M51) have been built to selectively kill cancer cells while eliciting potent antitumour immune responses. However, the mechanisms by which VSV∆M51 induces antitumour immunity are poorly understood. We employed intravital microscopy to study the association between cancer cell infection and tumour regression in multiple mouse tumour models. Surprisingly, we found that several tumours showing little evidence of cancer cell infection underwent complete regression. To investigate this further, I engineered VSV∆M51 infection-resistant tumour lines by knocking out the low-density lipoprotein receptor (LDL-R) gene family, known as the entry receptor for several oncolytic rhabdoviruses. Interestingly, mice bearing infection-resistant tumours still responded to VSV∆M51 therapy, suggesting that cancer cell infection is not required for therapeutic outcome. I then focused on understanding how VSV∆M51 elicits antitumour immunity in infection-resistant tumours. I found that VSV∆M51 treatment improved antigen presentation in the tumour draining lymph node (TdLN), since treating mice bearing mCherry+ tumours with VSV∆M51 induced migration of mCherry+ dendritic cells (DCs) to the TdLN. This migration was partially dependent on the systemic release of cytokines from the spleen, as VSV∆M51-induced DC recruitment to lymph nodes was attenuated in splenectomized mice. Congruently, I found that after transferring OT-I T cells into mice bearing OVA+ tumours, proliferation of OT-I T cells in the TdLN was increased post VSV∆M51 treatment. Together, these data suggest that VSV∆M51 infection of non-cancer cells enhances antitumour immunity by increasing antigen presentation and T cell activation in the TdLN. Finally, I asked how cancer cell infections, when present, contribute to antitumour immunity. To do this, I engineered cell lines that were hypersensitive to infection. In the absence of CD8+ T cells, VSV∆M51 infection within the tumour led to transient tumour regression, suggesting that these infections may cause oncolysis and debulking of the tumour. However, durable cures required CD8+ T cells. Further, the presence of an infectable tumour increased regression of a contralateral infection-resistant tumour, demonstrating that infection of cancer cells induces antitumour activity that can act at an abscopal site. Altogether, these data suggest that VSV∆M51 infection of both cancer and non-cancer cells contributes to antitumour immunity.