The role of non-cancer cell infections in oncolytic virus therapy

Oncolytic viruses (OV) are designed to seek out and kill cancer cells, while simultaneously inciting potent antitumour immunity. While their exact mechanism of action is incompletely understood, therapeutic activity is proposed to rely on viruses selectively infecting cancer cells - not only to debulk the tumour, but also to elicit immunogenic cell death (ICD) of cancer cells and subsequent antigen-specific immunity. However, despite being engineered for cancer cell selectivity, several studies have demonstrated OV-induced antitumour activity against tumours that do not robustly support virus infection in vivo. Further, many non-malignant cells within, and outside of, the tumour microenvironment (TME) have been shown to support OV infection, and in some cases, contribute to tumour regression. These unexpected findings warrant a more comprehensive understanding of the mechanisms by which OV-infected non-cancer cells elicit antitumour activity. Thus, in this review, we aim to summarize current knowledge on the role of non-cancer cell infections in OV therapy. We focus our attention primarily on infected non-cancer cells in the TME, including endothelial cells, fibroblasts and perivascular cells, as well as those in secondary lymphoid organs (spleen and lymph nodes). In addition, we include a brief commentary on the impact of liver and peripheral blood mononuclear cell infections. Interestingly, while the consequences of some non-malignant cell infections appear to be similar across multiple OVs, the outcome of other infections are OV-specific. This highlights the need to better understand cellular infections for each OV, in order to leverage this information for the development of next generation OV platforms.