Please use this identifier to cite or link to this item: 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
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