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Targeting tumor‐infiltrating Ly6G + myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma
Author(s) -
Chang ChunJung,
Yang YaoHsu,
Chiu ChiaoJuno,
Lu LiChun,
Liao ChienChia,
Liang CherWei,
Hsu ChihHung,
Cheng AnnLii
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31216
Subject(s) - sorafenib , hepatocellular carcinoma , medicine , cancer research , liver cancer , cd8 , proinflammatory cytokine , immune system , immunology , inflammation
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.