TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression
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Victor Ho1, Tong Seng Lim1, Justin Lee1, Jeffrey Steinberg3, Radoslaw Szmyd4,5, Muly Tham1, Jadegoud Yaligar3, Philipp Kaldis4,5, Jean-Pierre Abastado1,6, Valerie Chew1,2
1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
2Singhealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore
3Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
4Institute Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
5Department of Biochemistry, National University of Singapore (NUS), Singapore
6Institut de Recherches Internationales Servier, Suresnes, France
Valerie Chew, e-mail: [email protected]
Keywords: cancer immunotherapy, tumor microenvironment, local immune activation, hepatocellular carcinoma, combinatorial treatment
Received: April 01, 2015 Accepted: July 13, 2015 Published: July 23, 2015
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.
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