4-methylumbelliferone and interleukin-12 combined therapy inhibit tumor growth by inducing antitumor immunity and reducing the presence of cancer stem cells in an murine hepatocellular carcinoma model associated with fibrosis.

MALVICINI M ; RODRIGUEZ M; FIORE E; BAYO J; GARCIA MG; GOMEZ BUSTILLO S; ATORRASAGASTI C; PEIXOTO E; MAZZOLINI G

Conferencia; Conferencia Internacional de Inmunoterapia; 2016

, CRI-CIMT-EATI-AACR

The presence of immune cells as part of tumor microenvironment which includes many extracellular matrix (ECM) components and cancer cells may result in tumor growth inhibition. Then, the use of immunotherapy tools destined to generate or stimulates antitumor immunity has become an interesting therapeutic strategy for many tumor types. In this context, the excessive accumulation of ECM components including hyaluronan (HA), which typically occurs in liver cirrhosis, acts in synergy with different cells to promote hepatocarcinogenesis. Our aim was to evaluate the therapeutic effect of 4-methylumbelliferone (4Mu), a selective inhibitor of HA synthesis in combination with gene therapy of interleukin 12 mediated by an adenovirus (AdIL12) in a murine model of hepatocellular carcinoma (HCC) associated with advanced fibrosis induced by thioacetamide (TAA). Male C3H mice received an intrahepatic injection of 1,25×10e5 Hepa 129 cells (day 0) after 4 weeks of TAA administration (200 mg/kg). On day 5 mice were distributed in experimental groups (n = 8/group): saline; 4Mu 200 mg/Kg, drinking water (day 5); AdIL12 1×10e9 DICT50/ml, i.v (day 9) and 4Mu + AdIL-12. Antitumor efficacy and survival analyses were assesed. As a result, combined treatment induced a significant decrease of HCC tumor volume (p