Improving immunotherapy of hepatocellular carcinoma (HCC) using dendritic cells (DC) engineered to express IL-12 in vivo

Background Interleukin 12 (IL‐12), one of the most potent Th1‐cytokines, has been used to improve dendritic cells (DC)‐based immunotherapy of cancer. However, it failed to achieve clinical response in patients with hepatocellular carcinoma (HCC). In this study, improved conditions of immunotherapy with DC engineered to express IL‐12 were studied in murine subcutaneous HCC. Methods Tumour‐lysate pulsed DC were transduced with IL‐12‐encoding adenoviruses or cultivated with recombinant (r)IL‐12. DC were injected intratumourally, subcutaneously or intravenously at different stages of tumour‐development. Results Dendritic cell overexpressing IL‐12 by adenoviruses showed enhanced expression of costimulatory molecules and stronger priming of HCC‐specific effector cells than DC cultured with rIL‐12. Intratumoural but not systemic injections of IL‐12‐DC induced the strongest antitumoural effects reaching complete regressions in 75% of early‐staged tumours and in 33% of advanced tumours. Importantly, antitumoural effects could be further enhanced through combination with sorafenib. Analysing the tumour‐environment, IL‐12‐DC increased the levels of Th1‐cytokines/chemokines and of CD4+‐, CD8+‐T‐ and NK‐cells. Induced immunity was tumour‐specific and sustained since all tumour‐free animals were protected towards hepatic tumour‐cell rechallenge. However, IL‐12‐DC also enhanced immunosuppressive cytokines, regulatory T cells and even myeloid‐derived suppressor cells within the tumours. Conclusions Induced IL‐12‐overexpression by adenoviral vectors can effectively immunostimulate DC. Intratumoural but not systemic injection of activated IL‐12‐DC was crucial for effective tumour regression. The mechanism of this approach seems to be the induction of a sufficient Th1 tumour‐environment allowing the recruitment of effector cells rather than the inhibition of tumour immunosuppression. Thus, improved immunotherapy with IL‐12‐DC represents a promising approach towards HCC.