C07: Identification of molecular mechanisms conferring resistance to oncolytic viruses in HCC and implications for successful HCC virotherapy

In 2015, the first virotherapeutic drug (talimogene laherparepvec ) was approved for treatment of a highly immunogenic tumor (i.e. melanoma), constituting a hallmark in clinical development of virotherapy. However, thus far, virotherapy trials in patients with hepatocellular carcinoma (HCC) have not shown any breakthroughs. As a mechanism of action, virotherapeutics first induce a profound oncolysis being required to then trigger a profound antitumoral immune response. However, virotherapy-elicited immune responses are being widely inhibited in tumors exhibiting resistance to virotherapy. Preclinical work suggests that such resistances to virotherapy are mediated by localized immunosuppression within tumors through immunosuppressive myeloid cells 1. Expansion of theseimmunosuppressive myeloid cells is prompted by local accumulation of different cytokines and chemokines, including prostaglandin E2 (PGE2). Our own recent findings have shown that the chemokine CCL2 secreted from peritumoral precancerous senescent hepatocytes promotes growth of HCC by inhibiting NK cell function through myeloid cell-mediated immunosuppression2. Thus, also non-tumorous cells in the liver contribute to localized immunosuppression through cytokine production, demonstrating that peritumoral tissues play an important role in causing or enhancing resistance to antitumoral immune responses. This is particularly important for HCC, because HCC commonly develop in chronically inflamed livers, in which the cytokine and chemokine milieu of the tumor microenvironment is shaped not only by the tumor but also by the underlying inflammation of the liver. Therefore, in our project we are setting out to i) systematically identify critical pathways and immunosuppressive cell lineages mediating resistance to virotherapy in inflammationassociated HCC, ii) to therapeutically interfere with these resistance mechanisms, including the engineering of novel virotherapeutic vectors, and iii) to combine virotherapeutics and checkpoint inhibitors, because these two therapeutic approaches are ideal partners for combinatorial treatment regimens; while oncolytic viruses can cause induction of a tumor-specific T cell response, checkpoint inhibitors enhance the tumoricidal activity of T cells.