title: IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model.
abstract: Limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) was observed in clinical trials, thus prompting investigation into combination therapy. Interleukin-6 (IL-6) has important roles in modeling immune responses in cancers. Here, we hypothesized that IL-6 blockade would enhance antitumor immunity of HCC and synergize with anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor in treating HCC. The sources and immune modulating effects of IL-6 were investigated in HCC models. Combination of anti-IL-6 and anti-PD-L1 was tested in HCC bearing mice. We found that IL-6 is mainly secreted by cancer associated fibroblast (CAFs), but not tumor cells in HCC. High IL-6 expression CAFs could induce strong immunosuppression in HCC microenvironment by recruiting immunosuppressive cells, such as myeloid derived suppressive cells. In addition, high IL-6 expression CAFs also impaired tumor infiltrating T-cell function via upregulating inhibitory immune checkpoints. Using IL-6 blockade could reverse anti-PD-L1 resistance in HCC tumor model. In conclusion, our study indicates that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in HCC, providing a potential strategy to overcoming anti-PD-L1 resistance in HCC.
authors.affiliation: Department of Laparoscopy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Liu
authors.affiliation: The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Laparoscopy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. Electronic address: kl_6guo@126.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Lu
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000912:Antibodies, Neoplasm; D057134:Antibodies, Neutralizing; D060890:B7-H1 Antigen; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C498919:Cd274 protein, mouse; C577686:interleukin-6, mouse
keywords: Combinational therapy; Drug resistance; Hepatocellular carcinoma; IL-6; Immune checkpoint blockades; Immunology