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.
(Less)
- author
- Ho, Victor
; Lim, Tong Seng
; Lee, Justin
; Steinberg, Jeffrey
; Szmyd, Radoslaw
; Tham, Muly
; Yaligar, Jadegoud
; Kaldis, Philipp
LU
; Abastado, Jean Pierre
and Chew, Valerie
- publishing date
- 2015-07-23
- 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
- external identifiers
-
- scopus:84944448024
- pmid:26287667
- 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
- 2024-05-29 00:46:55
@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}},
keywords = {{Cancer immunotherapy; Combinatorial treatment; Hepatocellular carcinoma; Local immune activation; Tumor microenvironment}},
language = {{eng}},
month = {{07}},
number = {{29}},
pages = {{27252--27266}},
publisher = {{Impact Journals}},
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}},
}