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https://doi.org/10.18632/oncotarget.4583
Title: | TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression | Authors: | Ho, V Lim, T.S Lee, J Steinberg, J Szmyd, R Tham, M Yaligar, J Kaldis, P Abastado, J.-P Chew, V |
Keywords: | lysine stabilized polyinosinicpolycytidylic acid mitogen activated protein kinase protein kinase B sorafenib toll like receptor agonist unclassified drug antineoplastic agent carbanilamide derivative carboxymethylcellulose carboxymethylcellulose polycytidylic polyinosinic acid polylysine immunosuppressive agent mitogen activated protein kinase mitogen activated protein kinase kinase kinase nicotinamide polyinosinic polycytidylic acid polylysine protein kinase B sorafenib TLR3 protein, human toll like receptor 3 animal experiment animal model animal tissue antiproliferative activity Article cancer inhibition cell viability controlled study dendritic cell drug cytotoxicity drug efficacy drug mechanism drug response enzyme phosphorylation human human cell immune response immunogenicity in vitro study in vivo study liver cell carcinoma lymphocyte activation macrophage male mouse natural killer cell nonhuman signal transduction transposon tumor microenvironment agonists analogs and derivatives animal apoptosis C57BL mouse CD8+ T lymphocyte cell proliferation cell survival chemistry cytology disease course immune system liver cell carcinoma liver tumor metabolism nonobese diabetic mouse pathology phosphorylation SCID mouse tumor cell line Animals Antineoplastic Combined Chemotherapy Protocols Apoptosis Carboxymethylcellulose Sodium Carcinoma, Hepatocellular CD8-Positive T-Lymphocytes Cell Line, Tumor Cell Proliferation Cell Survival Disease Progression Extracellular Signal-Regulated MAP Kinases Humans Immune System Immunosuppressive Agents Liver Neoplasms Male MAP Kinase Kinase Kinases Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, SCID Niacinamide Phenylurea Compounds Phosphorylation Poly I-C Polylysine Proto-Oncogene Proteins c-akt Signal Transduction Toll-Like Receptor 3 |
Issue Date: | 2015 | Citation: | Ho, V, Lim, T.S, Lee, J, Steinberg, J, Szmyd, R, Tham, M, Yaligar, J, Kaldis, P, Abastado, J.-P, Chew, V (2015). TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression. Oncotarget 6 (29) : 27252-27266. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.4583 | 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 polyinosinicpolycytidylic- 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. | Source Title: | Oncotarget | URI: | https://scholarbank.nus.edu.sg/handle/10635/174138 | ISSN: | 19492553 | DOI: | 10.18632/oncotarget.4583 |
Appears in Collections: | Elements Staff Publications |
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