Description:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Interleukin 12 (<jats:styled-content style="fixed-case">IL</jats:styled-content>‐12), one of the most potent Th1‐cytokines, has been used to improve dendritic cells (<jats:styled-content style="fixed-case">DC</jats:styled-content>)‐based immunotherapy of cancer. However, it failed to achieve clinical response in patients with hepatocellular carcinoma (<jats:styled-content style="fixed-case">HCC</jats:styled-content>). In this study, improved conditions of immunotherapy with <jats:styled-content style="fixed-case">DC</jats:styled-content> engineered to express <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12 were studied in murine subcutaneous <jats:styled-content style="fixed-case">HCC</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Tumour‐lysate pulsed <jats:styled-content style="fixed-case">DC</jats:styled-content> were transduced with <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12‐encoding adenoviruses or cultivated with recombinant (r)<jats:styled-content style="fixed-case">IL</jats:styled-content>‐12. <jats:styled-content style="fixed-case">DC</jats:styled-content> were injected intratumourally, subcutaneously or intravenously at different stages of tumour‐development.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Dendritic cell overexpressing <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12 by adenoviruses showed enhanced expression of costimulatory molecules and stronger priming of <jats:styled-content style="fixed-case">HCC</jats:styled-content>‐specific effector cells than <jats:styled-content style="fixed-case">DC</jats:styled-content> cultured with <jats:styled-content style="fixed-case">rIL</jats:styled-content>‐12. Intratumoural but not systemic injections of <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12<jats:styled-content style="fixed-case">‐</jats:styled-content>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, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12‐<jats:styled-content style="fixed-case">DC</jats:styled-content> increased the levels of Th1‐cytokines/chemokines and of <jats:styled-content style="fixed-case">CD</jats:styled-content>4<jats:sup>+</jats:sup>‐, <jats:styled-content style="fixed-case">CD</jats:styled-content>8<jats:sup>+</jats:sup>‐T‐ and <jats:styled-content style="fixed-case">NK</jats:styled-content>‐cells. Induced immunity was tumour‐specific and sustained since all tumour‐free animals were protected towards hepatic tumour‐cell rechallenge. However, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12‐<jats:styled-content style="fixed-case">DC</jats:styled-content> also enhanced immunosuppressive cytokines, regulatory T cells and even myeloid‐derived suppressor cells within the tumours.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Induced <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12‐overexpression by adenoviral vectors can effectively immunostimulate <jats:styled-content style="fixed-case">DC</jats:styled-content>. Intratumoural but not systemic injection of activated <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12‐<jats:styled-content style="fixed-case">DC</jats:styled-content> 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 <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12‐<jats:styled-content style="fixed-case">DC</jats:styled-content> represents a promising approach towards <jats:styled-content style="fixed-case">HCC</jats:styled-content>.</jats:p></jats:sec>