目的：研究三氧化二砷（arsenic trioxide，As2O3）是否通过抑制髓系来源抑制性细胞（myeloid-derived suppressor cells，MDSCs）负向调控MDSCs诱导的肿瘤免疫耐受作用。方法： C57BL/6小鼠皮下注射黑素瘤B16细胞和肝癌H22细胞构建移植瘤模型，As2O3处理，观察移植瘤生长情况，流式细胞术检测荷瘤小鼠脾脏内MDSCs和其他免疫细胞的免疫表型，流式细胞术检测2 μmol/L As2O3对B16模型小鼠来源的MDSCs分化的影响。取B16模型小鼠随机分为As2O3处理及对照组，混合淋巴细胞反应检测MDSCs对T细胞免疫抑制活性的改变，ELISA检测B16模型小鼠血清及MDSCs培养上清中TNF-α、IL-10的水平。 结果： As2O3抑制B16和H22模型鼠的肿瘤生长，延长B16模型小鼠的生存期，并可显著下调小鼠脾脏内MDSCs的比例。体外经2 μmol/L As2O3处理5 d后，B16模型小鼠来源的MDSCs中成熟DCs(CD11c+CD40+)的比例较对照组显著升高\[（27.38±457）% vs （17.44±4.51）%，P=0.0078\]；As2O3组来源的MDSCs对T细胞的免疫抑制活性明显低于对照组（P=0.016）；As2O3组小鼠血清及MDSCs培养上清中TNF-α（F=5.78, P=0.014）和IL-10（F=17.83, P=0.045）的含量均较对照组显著降低。 结论：As2O3可通过诱导MDSCs向成熟表型分化、下调其免疫抑制活性等，负调控MDSCs的肿瘤免疫抑制功能。

Objective:To explore whether arsenic trioxide (As2O3) negatively regulate function of tumor immune tolerance induced with inhibiting myeloid-derived suppressor cells (MDSCs) through inhibition of the MDSCs. Methods: Melanoma B16 cells and liver cancer H22 cells were subcutaneously injected into the C57BL/6 mice respectively to construct xenograft models. Growth of the xenografts was observed after treatment with As2O3. Immunophenotypes of MDSCs and other immune cells in spleen tissues of the mice with the xenograft, and effect of As2O3 (2 μmol/L) on the differentiation of MDSCs in the mouse models with B16 cells were detected by flow cytometry assay. the mouse models with B16 cells were randomly divided into two groups, namely As2O3 treatment group and control group. Changes of immunosuppressive activity of T cell mediated by MDSCs were detected with mixed lymphocytes reaction. Concentrations of TNF-α and IL-10 in serum of the mouse model with B16 cells and supernatant of MDSCs cultures were detected by ELISA. Results: As2O3 could inhibit growth of the xenografts in the mouse models with B16 and H22 cells, prolong survival periods of the mouse models with B16 cells, and significantly decrease percentages of MDSCs in spleen of the mouse models. After treatment with As2O3 (2 μmol/L ) in vitro for 5 d, the proportion of mature DCs (CD11c+/CD40+) in MDSCs of the mouse models with B16 cells was significantly higher than that of mice in control group (\[27.38±4.57\]% vs \[17.44±4.51\]%，P=0.0078). The immunosuppressive activity of MDSCs against T cells in the As2O3 treatment group was significantly lower than that in the control group (P=0.016), and the concentrations of TNF-α and IL-10 in mouse serum of As2O3 treatment group and supernatant of MDSCs cultures were significantly lower than that of the control group. Conclusion: As2O3 could induce maturation of MDSCs, down regulate its immunosuppressive activity and negatively regulate tumor suppression function of MDSCs.

上海市科委自然科学基金资助项目（No.13ZR1405000）