TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression

Abstract

// Victor Ho 1 , Tong Seng Lim 1 , Justin Lee 1 , Jeffrey Steinberg 3 , Radoslaw Szmyd 4, 5 , Muly Tham 1 , Jadegoud Yaligar 3 , Philipp Kaldis 4, 5 , Jean-Pierre Abastado 1, 6 , Valerie Chew 1, 2 1 Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore 2 Singhealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore 3 Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore 4 Institute Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore 5 Department of Biochemistry, National University of Singapore (NUS), Singapore 6 Institut de Recherches Internationales Servier, Suresnes, France Correspondence to: Valerie Chew, e-mail: Valerie.chew.s.p@singhealth.com Keywords: cancer immunotherapy, tumor microenvironment, local immune activation, hepatocellular carcinoma, combinatorial treatment Received: April 01, 2015      Accepted: July 13, 2015      Published: July 23, 2015 ABSTRACT Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro , in association with impaired phosphorylation of AKT, MEK and ERK. In vivo , the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8 + T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies.