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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2μmol/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2μmol/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 investigate whether arsenic trioxide (As_2O_3) negatively regulates the immune tolerance induced by MDSCs by inhibiting myeloid-derived suppressor cells (MDSCs). Methods: C57BL / 6 mice were inoculated subcutaneously with melanoma B16 cells and H22 hepatoma cells to construct xenograft model. The growth of xenografts was observed with As_2O_3 treatment. The immunofluorescence of MDSCs and other immune cells in the spleen of mice with tumor were detected by flow cytometry The effect of 2μmol / L As_2O_3 on the differentiation of MDSCs derived from B16 mice was detected by flow cytometry. The B16 model mice were randomly divided into As 2 O 3 treatment group and control group. The changes of immunosuppressive activity of T cells by mixed lymphocyte reaction were detected by mixed lymphocyte reaction. The levels of TNF-α and IL-10 in the serum of B16 mice and the supernatant of MDSCs were determined by ELISA Level. Results: As 2 O 3 inhibited the tumor growth of B16 and H22 mice, prolonged the survival of B16 mice and significantly down-regulated the proportion of MDSCs in mice spleen. After treatment with 2μmol / L As_2O_3 for 5 days, the percentage of mature DCs (CD11c ~ + CD40 ~ +) in B16 model mice was significantly higher than that in control group [(27.38 ± 4.57)% vs (17.44 ± 4.51) %, P = 0.0078]. The immunosuppressive activity of MDSCs derived from As_2O_3 group on T cells was significantly lower than that of the control group (P = 0.016) = 0.014) and IL-10 (F = 17.83, P = 0.045) were significantly lower than the control group. CONCLUSION: As2O3 can down-regulate the immunosuppressive function of MDSCs by inducing MDSCs to differentiate into mature phenotype and down-regulating their immunosuppressive activities.