TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression.
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.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Victor
V
Ho
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Tong Seng
TS
Lim
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Justin
J
Lee
Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Jeffrey
J
Steinberg
Institute Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Department of Biochemistry, National University of Singapore (NUS), Singapore.
Radoslaw
R
Szmyd
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Muly
M
Tham
Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Jadegoud
J
Yaligar
Institute Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Department of Biochemistry, National University of Singapore (NUS), Singapore.
Philipp
P
Kaldis
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Institut de Recherches Internationales Servier, Suresnes, France.
Jean-Pierre
JP
Abastado
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Singhealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd., Singapore.
Valerie
V
Chew
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007107:Immune System; D007166:Immunosuppressive Agents / Q000737:chemistry; D008113:Liver Neoplasms / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000737:chemistry; D010766:Phosphorylation; D011070:Poly I-C / Q000737:chemistry*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D051196:Toll-Like Receptor 3 / Q000819:agonists*
D007166:Immunosuppressive Agents; D010671:Phenylurea Compounds; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011107:Polylysine; D009536:Niacinamide; C019531:poly ICLC; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
cancer immunotherapy; combinatorial treatment; hepatocellular carcinoma; local immune activation; tumor microenvironment