Abstract
Currently, the benefits of immune checkpoint blockade (ICB) for hepatocellular carcinoma (HCC) are restricted to a subset of patients. We hypothesized that co-treatment with the inflammatory oncolytic virus (OV) vesicular stomatitis virus (VSV-IFNβ) would reprogram the highly immunosuppressive tumor microenvironment (TME) to enhance ICB. However, VSV-IFNβ inhibited the efficacy of ICB. To develop better, mechanism-based immunotherapies for HCC, here, we characterized (1) the baseline T cell response to HCC, (2) its enhancement by ICB, (3) the inhibitory effects of VSV, and (4) the antigenic response of HCC to treatment. We show that a slowly developing anti-tumor CD8+ T cell response becomes exhausted, is only initially sensitive to ICB, is outcompeted by a strong anti-viral CD8+ T cell response against VSV-IFNβ, and combination with ICB boosted the anti-viral, as opposed to the anti-tumor, response. We also identify additional molecules (CD39, LAG3) that may be valuable therapeutic targets to combine with ICB. Finally, we show that Sleeping Beauty (SB)-HCC tumors evolve different antigenic/immunogenic profiles to evade different therapies. Therefore, the future immunotherapy of HCC should target multiple molecules/immune checkpoints, avoid attritional competition by immunodominant T cells, and account for the rapidly evolving tumor phenotypes that emerge as a result of treatment-selective pressures.