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

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.

Alternative MyD88 -Cyclin D1 signaling in breast cancer cells regulates TLR3 mediated cell proliferation

“…This reported tumor suppressive and apoptotic effect of TLR3 is achieved predominantly by induction of type I IFN and activation of effector cells, when TLR3 is located within the endosomal compartment (Bugge et al, 2017; Gambar et al, 2014; Braunstein et al, 2018). TLR3 synthetic ligand poly-ICLC with Sorafenib significantly reduces tumor growth, both in-vitro and in-vivo in hepatocellular carcinoma (Ho et al, 2015). The mechanistic of anti-tumorigenic effect of TLR3 is well established, wherein TRIF dependent classical pathway induces apoptosis in cancer cells through the endosomal compartment.…”

“…TLR3 agonists have been used in immunotherapy for various clinical and preclinical studies. The majority of clinical studies establish TLR3 as a tumor suppressor using synthetic ligand poly(I:C) or poly-ICLC for adjuvant therapy or targeted therapy (Jia and Wang 2015; Braunstein et al, 2018; Ho et al, 2015, Schau et al, 2019). Ligand binding has been reported to induce endosomal TLR3 mediated recruitment of TIR domain-containing adapter-inducing interferon β (TRIF) (O’Neill and Bowie 2007) to trigger type-I IFN and to induce cellular apoptosis (Conforti et al, 2010; Salaun et al, 2006; Gambara et al, 2014; Oshiumi et al, 2003; Yamamoto 2003).…”

Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword

“…In addition to having direct anti-tumoral effects on tumor cell death, the TLR3 effect could be mediated by immune cells (Chew et al, 2012;Ho et al, 2015;Xu et al, 2013b). In colon carcinoma and HCC mouse models, poly I:C injection produced an anti-tumoral effect via the recruitment of NK and CD8 + T cells (Chew et al, 2012;Takemura et al, 2015) and activated CD4 + T cells (Ho et al, 2015).…”

“…In colon carcinoma and HCC mouse models, poly I:C injection produced an anti-tumoral effect via the recruitment of NK and CD8 + T cells (Chew et al, 2012;Takemura et al, 2015) and activated CD4 + T cells (Ho et al, 2015). In a murine model of lung cancer, TLR3 stimulation by poly I:C decreased tumor progression by a mechanism implying the conversion of pro-tumoral myeloid cells into M1 macrophages with tumoricidal properties (Shime et al, 2012).…”

Advanced Combinatorial Radioimmunogenetic Therapy for Cancer

“…Gene therapy for cancer is improving slowly. This technology has already shown promising impact in the world of oncology [22][23][24][25][26][27][28][29][30][31][32]. New powerful technology like TALENS, CRISPR/cas9 system paves the way in successful delivery to the targeted tumour cell.…”