Targeting tumor‐infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma

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. What's new? The multi‐kinase inhibitor sorafenib is an approved agent for the treatment of liver cancer. Using a syngeneic mouse liver cancer model, the authors found less therapeutic efficacy of sorafenib in orthotopic liver tumors as compared to subcutaneous tumors. They attributed this to increased levels of proinflammatory cytokines and immunosuppressive myeloid‐derived suppressor cells found in orthotopic tumors, conditions that when suppressed increased sorafenib's therapeutic efficiency. The authors propose targeting the immunosuppressive tumor microenvironment as a novel therapeutic approach for liver cancers.