IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model

• Published in: Biochemical and biophysical research communications Vol. 486; no. 2; pp. 239 - 244
• Main Authors: Liu, Hu, Shen, Jun, Lu, Kai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-04-2017
• Subjects: Animals; Antibodies, Neoplasm - pharmacology; Antibodies, Neutralizing - pharmacology; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Cancer-Associated Fibroblasts - drug effects; Cancer-Associated Fibroblasts - immunology; Cancer-Associated Fibroblasts - pathology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Combinational therapy; Disease Models, Animal; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Humans; IL-6; Immune checkpoint blockades; Immunology; Injections, Subcutaneous; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - genetics; Interleukin-6 - immunology; Liver Neoplasms - genetics; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Male; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Signal Transduction; Tumor Microenvironment - drug effects; Immune checkpoint blockades; Hepatocellular carcinoma; Immunology; Drug resistance; Combinational therapy; IL-6
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.02.128

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.
•IL-6 was highly expressed in CAFs but not HCC tumor cells.•IL-6 expressed by CAFs promoted the development of HCC in mouse model.•IL-6 expressed by CAFs promoted the recruiting of immunosuppressive cells in HCC.•IL-6 expressed by CAFs impaired tumor-infiltrating T cells' function.•IL-6 reversed anti-PD-L1 resistance in HCC mouse model.