Abstract
Abstract Background]: The mechanisms underlying the inherent or acquired resistance to sorafenib in advanced hepatocellular carcinoma (HCC) are not fully understood. We studied the role of myeloid-derived suppressor cells (MDSCs), a subset of bone marrow cells with immune-suppressive and proangiogenic activities, in sorafenib-treated mice and patients. Materials and Methods: An orthotopic mouse liver cancer model was established by implanting BNL cells to BALB/cByJNarl mice. Liver tumor-bearing mice were treated with sorafenib (5 mg/kg/d) for 1 week or 3 weeks from the day 8 after tumor cells implantation. For combination therapy, mice were treated sorafenib and anti-IL-6 Ab or its isotype control Ab (500 μg/every 3 days starting from day 4 for 4 doses). Tumor-infiltrating leukocytes (TILs) and leukocytes of other tissues including liver, spleen, peripheral blood, and bone marrow were isolated, and characterized by flow cytometry analysis. Morphological characteristics of MDSCs were determined by cytospin and Liu staining. Pro-inflammatory cytokines were detected by ELISA or mouse inflammatory cytokines beads array (BD). Paired HCC tissues from advanced HCC patients treated with sorafenib (before and post-sorafenib progression tissues) were evaluated for the expression of CD11b, CD15, and CD66b in TILs by immunohistochemistry. Results: In mice treated with sorafenib, the CD11b+Gr1+Ly6G+ MDSCs were significantly increased in liver tumors, but not in others tissues. Morphologically, these MDSCs were segmented nuclear PMN type cells. The analysis of TILs revealed that the percentage of total immune effectors (CD4+ or CD8+ IFN-γ-expressing T cells) versus total immune suppressors (IL-10 or TGF β-expressing CD4+ T cell, FOXP3-expressing CD4+ T cells) was lower in the tumors of sorafenib-treated mice than those of the vehicle-treated mice. The T cell proliferation capability was also significantly decreased in TILs of sorafenib-treated mice versus TILs of vehicle-treated mice. Multiple inflammatory cytokines including VEGF, G-CSF, MCP-1, and IL-6 were significantly increased in mouse liver tumors treated with sorafenib. When combined with sorafenib, anti-IL-6 antibody alleviated the early tumor-infiltration of Ly6G+ MDSCs, restored the proliferative activity of TILs, decreased the levels of pro-inflammatory factors in tumors, and suppressed the liver tumor growth synergistically. In 6 paired human HCC tissues, we found that 3 exhibited higher proportion of CD11b, CD15, or CD66b+ cells in post-sorafenib progression tissues than their pre-sorafenib treatment tissues. Conclusions: Our data indicate that tumor-infiltrating PMN type MDSCs and associated immunosuppression may be an important mechanism impeding the therapeutic efficacy of sorafenib in HCC. (This works was supported by MOST 105-2314-B-002-180). Citation Format: Chun-Jung Chang, Li-Chun Lu, Cher-wei Liang, Chih-Hung Hsu, Ann-Lii Cheng. Tumor-infiltrating PMN-MDSCs mediate sorafenib resistance in hepatocellular carcinoma through immune suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2017-2067
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