Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide. Combination immunotherapy is now standard of care for advanced HCC, improving patient outcomes. However, a considerable number of patients remain unresponsive, or are unable to tolerate therapy. Tyrosine kinase inhibitors (TKIs), such as the former first-line agent sorafenib, remain an option for such patients, yet provide only marginal efficacy. We hypothesised that a clinically advanced immunogenic oncolytic virus, namely, human Orthoreovirus, might improve TKI mediated therapy. Surprisingly, uv-inactivated, replication-deficient reovirus, but not live virus, significantly extended survival when combined with sorafenib in preclinical immunocompetent HCC models. Favourable responses were dependent upon adaptive immunity, mediated by IFNB-induced skewing of the infiltrating T-cell ratio in favour of cytotoxic CD4+ T-cells expressing granzyme B and perforin. Interestingly, this subset effectively killed tumours via both contact juxtacrine and paracrine processes, the former being MHCII independent. Moreover, efficacy correlated with more rapid and robust IFN production by inactivated virus due to the absence of innate viral antagonists. Thus, we reveal a means to improve TKI-HCC outcomes through an alternative virus-driven immunotherapy, underpinned by non-classical immunological mechanisms.
Publisher
Cold Spring Harbor Laboratory