Abstract 461: Therapeutic effect of sorafenib is attenuated by tumor-infiltrating Ly6G+ myeloid-derived suppressor cells (MDSCs) and is restored by anti-interleukin-6 (IL-6) antibody treatment in an orthotopic mouse liver cancer model
Authors: Chang Chun-Jung , Yang Yao-Hsu , Chiu Chiao-Juno , Chiang Bor-Luen , Lee Xiao-yi , Hsu Chih-Hung , Cheng Ann-Lii 
Published: August 2015

Purpose: CD11b+Gr1+ MDSC, a subset of bone marrow cells with immune-suppressive and proangiogenic activities, has been shown to mediate resistance to antiangiogenic therapy in various cancer models. The significance of tumor-infiltrating MDSCs in mediating the resistance to sorafenib in hepatocellular carcinoma (HCC) has not been elucidated.

Experimental designs: We adopted an orthotopic mouse liver cancer model by implanting BNL murine liver cancer cells in BALB/c mice, which were treated with sorafenib at the dose of 5 mg/Kg/d from day 8 after tumor cells implantation for 1 week or 3 weeks.

Results: Both proportion and number of CD11b+Gr1+Ly6G+Ly6Clo MDSCs markedly increased in liver tumors, but not in spleens. This increment of tumor-infiltrating CD11b+Gr1+Ly6G+Ly6Clo MDSCs was found at one week of sorafenib treatment, when intra-tumor levels of multiple proangiogenic factors including VEGF, MCP-1 and IL-6 significantly increased, and the ratios of immune suppressors versus interferon-gamma expressing effectors tilted toward immune-suppression. CD11b+Gr1+Ly6G+Ly6Clo MDSCs isolated from liver tumors treated with sorafenib expressed higher levels of CD115, CD124, CD274 or CCR2 on cell surface and higher transcripts of pro-angiogenic factors, including VEGF, COX2, Bv8/Prok2, STAT3, S100A8, S100A9, or NOX2 than those from liver tumors treated with vehicle. Tumor-derived CD11b+Gr1+Ly6G+Ly6Clo MDSCs from sorafenib-treated mice were capable of suppressing specific tumor cell killing of CD8+ T cells and inducing the generation of immunosuppressive CD4+ T cells. These MDSCs also induced angiogenesis, as demonstrated in increased vascular density and hemoglobin. In sorafenib- treated mice, the concomitant use of anti-IL-6 antibody alleviated the early infiltration of CD11b+Gr1+Ly6G+Ly6Clo MDSCs in liver tumors, decreased the levels of anti-angiogenic factors, reduced vascular density, restored the proliferative activity of tumor-infiltrating T cells and suppressed the liver tumor growth synergistically.

Conclusions: Our data indicate that intratumor infiltration of CD11b+Gr1+Ly6G+Ly6Clo MDSCs impaired the therapeutic efficacy of sorafenib through promoting immune-suppression and angiogenesis. Targeting this subset of MDSCs by anti-IL-6 antibody could improve the anti-HCC efficacy of sorafenib.(This work was supported by Grant. NSC 102-2314-B-002 -144 -)

Citation Format: Chun-Jung Chang, Yao-Hsu Yang, Chiao-Juno Chiu, Bor-Luen Chiang, Xiao-yi Lee, Chih-Hung Hsu, Ann-Lii Cheng. Therapeutic effect of sorafenib is attenuated by tumor-infiltrating Ly6G+ myeloid-derived suppressor cells (MDSCs) and is restored by anti-interleukin-6 (IL-6) antibody treatment in an orthotopic mouse liver cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 461. doi:10.1158/1538-7445.AM2015-461