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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.

Publications

Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, Medina-Echeverz J, Longerich T, Forgues M, Reisinger F, Heikenwalder M, Wang XW, Zender L, Greten TF (2016) Distinct functions of senescenceassociated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30:533-47.
Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M, Han M, Thornton AM, Zhang H, Egger M, Luo J, Felsher DW, McVicar DW, Weber A, Heikenwalder M, Greten TF (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253-7.
Ji J, Eggert T, Budhu A, Forgues M, Takai A, Dang H, Ye Q, Lee JS, Kim JH, Greten TF, Wang XW (2015) Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 62:481-95.
Medina-Echeverz J, Ma C, Duffy AG, Eggert T, Hawk N, Kleiner DE, Korangy F, Greten TF (2015) Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage. Cancer Immunol Res 3:557-66.
Ruf B, Berchtold S, Venturelli S, Burkard M, Smirnow I, Prenzel T, Henning SW, Lauer UM (2015) Combination of the HDACi resminostat with oncolytic measles virus as a new option for epivirotherapeutic treatment of hepatocellular carcinoma. Mol Ther Oncolytics 7;2:15019. 348
Eggert T, Medina-Echeverz J, Kapanadze T, Kruhlak MJ, Korangy F, Greten TF (2014) Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage. PLoS One 9:e112717.
Weiland T, Lampe J, Essmann F, Venturelli S, Berger A, Bossow S, Berchthold S, Schulze-Osthoff K, Lauer UM, Bitzer M (2014) Enhanced killing of therapy-induced senescent tumor cells by oncolytic Measles vaccine viruses. Int J Canc 134:235-243.
Yurttas C, Berchtold S, Malek NP, Bitzer M, Lauer UM (2014) Pulsed versus continuous application of the prodrug 5-fluorocytosine to enhance the oncolytic effectiveness of a measles vaccine virus armed with a suicide gene. Hum Gene Ther Clin Dev 25:85-96.
Bach P, Abel T, Hoffmann C, Gal Z, Braun G, Voelker I, Ball CR, Johnston IC, Lauer UM, Herold- Mende C, Mühlebach MD, Glimm H, Buchholz CJ (2013) Specific Elimination of CD133+ Tumor Cells with Targeted Oncolytic Measles Virus. Cancer Res 73:865-874.
Lampe J, Bossow S, Weiland T, Smirnow I, Lehmann R, Neubert W, Bitzer M, Lauer UM (2013) An armed oncolytic measles vaccine virus eliminates human hepatoma cells independently of apoptosis. Gene Ther 20:1033-41.