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 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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second most frequent cause of cancer-related death worldwide [1]
The multi-kinase inhibitor Sorafenib is currently the only FDA-approved drug available for the treatment of advanced HCC [31], and here we demonstrate that the poor clinical efficacy of Sorafenib can be significantly enhanced by simultaneous administration of the Toll-like receptor-3 (TLR3) agonist poly-ICLC
These data are consistent with our previous report that TLR3 agonists are promising candidates for immunotherapy in HCC due to their ability to directly induce tumor cell death and activate host immune responses in the tumor microenvironment [11]
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second most frequent cause of cancer-related death worldwide [1]. Recent studies have reported the emergence of HCC resistance to Sorafenib treatment that is associated with enhanced metastatic potential of tumor cells and subsequent relapse after prolonged treatment [3, 4]. Several studies have shown that Sorafenib induces host immunosuppression by impairing the activation of natural killer (NK) cells and dendritic cells (DC) [6, 7]. Other studies have indicated that Sorafenib is able to reduce the proportion of PD-1-expressing CD8+ T cells and decreases the number and function of regulatory T cells (Treg) in the tumor microenvironment [8]. Since the balance of immune responses in the tumor microenvironment is known to be a critical determinant of tumor progression, it will be important to better understand the immuno-modulatory effects of Sorafenib and to determine if methods of promoting host immune response could increase its efficacy
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
