Oncolytic reovirus-mediated recruitment of early innate immune response reverses immunotherapy-resistance in prostate tumours by inducing a T-cell inflamed microenvironment

Abstract Prostate cancers are considered ‘cold’ tumours characterised by minimal T-cell infiltrates, absence of a type-I IFN signature and the presence of immunosuppressive cells. This non-inflamed phenotype is likely responsible for the lack of sensitivity of prostate cancer patients to immune checkpoint blockade (ICB) therapy. Oncolytic virus therapy can potentially overcome this resistance to immunotherapy in prostate cancers by transforming cold tumours into ‘hot’, immune cell-infiltrated tumours. We investigated whether the combination of intratumoural oncolytic reovirus, followed by targeted blockade of PD-1 checkpoint inhibition and/or the immunomodulatory CD73/Adenosine system can enhance anti-tumour immunity. Treatment of subcutaneous TRAMP-C2 prostate tumours with combined intratumoral reovirus and anti-PD-1 or anti-CD73 antibody significantly enhanced survival of mice compared to reovirus or either antibody therapy alone. Only combination therapy led to rejection of pre-established tumours and protection from tumour re-challenge. This therapeutic effect was dependent on CD4+T-cells and NK-cells. Nanostring immune-profiling of tumours confirmed that reovirus increased tumour immune cell infiltration and revealed an upregulation of the immune-regulatory receptor, BTLA. This expression of BTLA on innate APCs and its ligand, HVEM, on T-cells from reovirus-infected tumours was in-keeping with a role for the HVEM-BTLA pathway in promoting the potent anti-tumour memory response observed.