A successful therapy combining tumor microenvironment remodeling and activation of immune response inhibits tumor growth in a murine model of hepatocellular carcinoma associated with fibrosis

MARCELO RODRIGUEZ; JUAN BAYO; ESTEBAN FIORE; SOFIA GOMEZ BUSTILLO; MARIANA MALVICINI; GUILLERMO MAZZOLINI

Congreso; LXI Reunion Anual de la Sociedad Argentina de Investigaciones Clinicas (SAIC); 2016

SAIC

Currently, strategies for targeting the interaction between tumor microenvironment components that includes tumor cells, fibroblasts, endothelial, immune and cancer stem cells (CSCs) and the extracellular matrix (ECM), could delay tumor progression. In fact, immunotherapy to activates antitumor response and inhibits tumor growth is an attractive option. Liver fibrosis, a pre-neoplastic condition for hepatocellular carcinoma (HCC) is usually accompanied with the accumulation of ECM components including hyaluronan (HA). Our aims were to evaluate the effects of 4-methylumbelliferone (4Mu), an inhibitor of HA synthesis combined with gene therapy of interleukin 12 mediated by an adenovirus (AdIL-12) in a murine model of HCC associated with fibrosis induced by thioacetamide (TAA). C3H mice received Hepa129 cells intrahepatically (day 0) after 4 weeks of 200mg/kg TAA administration. On day 5 mice were distributed in groups (n=8/group): saline; 4Mu 200 mg/Kg, drinking water (day 5); AdIL-12 1x10e9 DICT50/ml, i.v (day 9) and 4Mu + AdIL-12. Antitumor efficacy and survival were studied. Liver and spleen samples were taken to determine prevalence and function of immune cells and the expression of CSCs markers. Combined treatment induced a significant decrease of HCC growth (p