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

Ho, Victor ; Lim, Tong Seng ; Lee, Justin ; Steinberg, Jeffrey ; Szmyd, Radoslaw ; Tham, Muly ; Yaligar, Jadegoud ; Kaldis, Philipp LU ; Abastado, Jean Pierre and Chew, Valerie (2015) In Oncotarget 6(29). p.27252-27266
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cancer immunotherapy, Combinatorial treatment, Hepatocellular carcinoma, Local immune activation, Tumor microenvironment
in
Oncotarget
volume
6
issue
29
pages
27252 - 27266
publisher
Impact Journals, LLC
external identifiers
  • pmid:26287667
  • scopus:84944448024
ISSN
1949-2553
DOI
10.18632/oncotarget.4583
language
English
LU publication?
no
id
b123935b-38e3-4ea2-99ac-eb6bec26680e
date added to LUP
2019-09-18 13:50:04
date last changed
2021-02-23 03:22:20
@article{b123935b-38e3-4ea2-99ac-eb6bec26680e,
  abstract     = {<p>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<sup>+</sup> 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.</p>},
  author       = {Ho, Victor and Lim, Tong Seng and Lee, Justin and Steinberg, Jeffrey and Szmyd, Radoslaw and Tham, Muly and Yaligar, Jadegoud and Kaldis, Philipp and Abastado, Jean Pierre and Chew, Valerie},
  issn         = {1949-2553},
  language     = {eng},
  month        = {07},
  number       = {29},
  pages        = {27252--27266},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression},
  url          = {http://dx.doi.org/10.18632/oncotarget.4583},
  doi          = {10.18632/oncotarget.4583},
  volume       = {6},
  year         = {2015},
}