College of Pharmacy, Chungbuk National University, Cheongju, 361-763, South Korea.
Arch Pharm Res. 2014;37(9):1234-40. doi: 10.1007/s12272-014-0379-4. Epub 2014 Apr 19.
Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice, subsequently suppressing the host immune system. MDSCs represent a group of immature myeloid cells expressing CD11b and Gr-1. Here, we show that a Toll-like receptor (TLR) agonist, resiquimod, which binds to TLR7 and TLR8, induces the differentiation of MDSCs into mature myeloid cells. MDSCs were isolated from mice bearing mammary carcinoma 4T1 cells, and the purified MDSCs were cultured in the presence of resiquimod for 5 days. Phenotypic analysis showed that the resiquimod-treated MDSCs differentiated into F4/80⁺ macrophages and CD11c⁺/I-A(d⁺) dendritic cells. Functional analysis showed that the MDSCs also lost their suppressive activity on T cells. Resiquimod-treated MDSCs significantly enhanced the proliferation of T cells that were treated with anti-CD3 and anti-CD28 monoclonal antibodies. These results show that resiquimod induces the differentiation of MDSCs into macrophages and dendritic cells, and also suggest that resiquimod may improve cancer immunotherapy by reducing immunosuppressive MDSCs.
髓系来源的抑制细胞（MDSCs）在癌症患者和荷瘤小鼠中积累，随后抑制宿主免疫系统。MDSCs 是一群表达 CD11b 和 Gr-1 的未成熟髓系细胞。在这里，我们表明 Toll 样受体（TLR）激动剂瑞喹莫德（resiquimod）与 TLR7 和 TLR8 结合，诱导 MDSCs 向成熟髓系细胞分化。我们从患有乳腺癌 4T1 细胞的小鼠中分离出 MDSCs，并在瑞喹莫德存在的情况下将纯化的 MDSCs 培养 5 天。表型分析表明，瑞喹莫德处理的 MDSCs 分化为 F4/80⁺巨噬细胞和 CD11c⁺/I-A(d⁺)树突状细胞。功能分析表明，MDSCs 也失去了对 T 细胞的抑制活性。瑞喹莫德处理的 MDSCs 显著增强了用抗 CD3 和抗 CD28 单克隆抗体处理的 T 细胞的增殖。这些结果表明，瑞喹莫德诱导 MDSCs 向巨噬细胞和树突状细胞分化，并提示瑞喹莫德可能通过减少免疫抑制性 MDSCs 来改善癌症免疫治疗。
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