Targeting tumor-infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma
Journal
International Journal of Cancer
Journal Volume
142
Journal Issue
9
Pages
1878-1889
Date Issued
2018
Author(s)
Abstract
Sorafenib, a multikinase inhibitor with antiangiogenic activity, is an approved therapy for hepatocellular carcinoma (HCC). It is unclear whether the proinflammatory and immunosuppressive mechanisms may limit the therapeutic efficacy of sorafenib in HCC. We used a syngeneic mouse liver cancer cell line to establish orthotopic liver or subcutaneous tumors to study how proinflammatory and immunosuppressive mechanisms impact on the efficacy of sorafenib. We found sorafenib exhibited a potent therapeutic effect in subcutaneous tumors, but a less potent effect in orthotopic liver tumors. The protein levels of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGF-A) were persistently elevated in orthotopic liver tumors, but not in subcutaneous tumors, treated with sorafenib. Likewise, the tumor-infiltrating Ly6G+ myeloid-derived suppressor cells (MDSCs) and immune suppressors were increased in orthotopic liver tumors, not in subcutaneous tumors, treated with sorafenib. The tumor-infiltrating Ly6G+ MDSCs of sorafenib-treated orthotopic liver tumors significantly induced IL-10 and TGF-β expressing CD4+ T cells, and downregulated the cytotoxic activity of CD8+ T cells. IL-6, but not VEGF-A, protected Ly6G+ MDSCs from sorafenib-induced cell death in vitro. The combination of anti-Ly6G antibody or anti-IL-6 antibody with sorafenib significantly reduced the cell proportion of Ly6G+ MDSCs in orthotopic liver tumors, enhanced the T cells proliferation and improved the therapeutic effect of sorafenib synergistically. Modulating tumor microenvironment through targeting tumor-infiltrating Ly6G+MDSCs represents a potential strategy to improve the anti-HCC efficacy of sorafenib. ? 2017 UICC
SDGs
Other Subjects
interleukin 10; interleukin 6; interleukin 6 antibody; neutralizing antibody; sorafenib; transforming growth factor beta; vasculotropin A; antineoplastic agent; interleukin 6; interleukin-6, mouse; Ly antigen; Ly6G antigen, mouse; neutralizing antibody; sorafenib; vascular endothelial growth factor A, mouse; vasculotropin A; animal cell; animal experiment; animal model; animal tissue; Article; cancer tissue; CD4+ T lymphocyte; CD8+ T lymphocyte; cell death; cell isolation; cell mediated cytotoxicity; controlled study; down regulation; drug efficacy; flow cytometry; immunosuppressive treatment; in vitro study; liver cancer cell line; liver cell carcinoma; loading drug dose; lymphocyte proliferation; male; mouse; myeloid-derived suppressor cell; nonhuman; priority journal; reverse transcription polymerase chain reaction; tumor associated leukocyte; tumor microenvironment; animal; Bagg albino mouse; bone marrow cell; drug effect; experimental liver neoplasm; immunology; metabolism; transgenic mouse; tumor cell line; Animals; Antibodies, Neutralizing; Antigens, Ly; Antineoplastic Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Interleukin-6; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Myeloid Cells; Sorafenib; Vascular Endothelial Growth Factor A
Publisher
Wiley-Liss Inc.
Type
journal article