间充质基质细胞对促肿瘤中性粒细胞发育的编程作用
Programming of the development of tumor-promoting neutrophils by mesenchymal stromal cells.
作者信息
Hu Xiaoyu, Zhou Yushan, Dong Kui, Sun Zhina, Zhao Dan, Wang Weiqiang, Yu Gang, Liu Wentian, Xu Guogang, Han Zhongchao, Feng Xiaoming
机构信息
State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences, Tianjin, P.R. China.
出版信息
Cell Physiol Biochem. 2014;33(6):1802-14. doi: 10.1159/000362959. Epub 2014 May 27.
BACKGROUND/AIMS: Neutrophils obtain immunosuppressive function during tumor development, yet the mechanisms are largely unknown. This study explored whether and how mesenchymal stromal cells (MSCs), the key component of tumor microenvironment, regulate the suppressive function of neutrophils.
METHODS
Immunosuppressive function of neutrophils was evaluated by T cell proliferation assay and 4T1 breast tumor model; molecular mechanisms were explored by transcriptional profiling, Real-time RT-PCR, arginase activity assay, and iNOS inhibition experiments.
RESULTS
After being cocultured with MSCs primed by TNF-α (TNF-MSCs), CD11b(+)Ly6G(+) neutrophils isolated from bone marrow of normal mice or spleen of tumor-bearing mice obtained immunosuppressive function to inhibit T cell proliferation in vitro, and to enhance 4T1 tumor progression in vivo. Moreover, arginase activity and expression of iNOS, saa3, some cytokines and chemokines and their receptors, were upregulated in neutrophils after co-culture with TNF-MSCs. Inhibition of iNOS activity attenuated the suppressive effect of TNF-MSC pre-cocultured neutrophils on T cell proliferation.
CONCLUSION
MSCs program neutrophils into an immunosuppressive and tumor-promoting phenotype.
背景/目的：中性粒细胞在肿瘤发展过程中获得免疫抑制功能，但其机制尚不清楚。本研究探讨肿瘤微环境的关键成分间充质基质细胞（MSCs）是否以及如何调节中性粒细胞的抑制功能。
方法
通过T细胞增殖试验和4T1乳腺肿瘤模型评估中性粒细胞的免疫抑制功能；通过转录谱分析、实时逆转录-聚合酶链反应、精氨酸酶活性测定和诱导型一氧化氮合酶抑制实验探索分子机制。
结果
从正常小鼠骨髓或荷瘤小鼠脾脏分离的CD11b(+)Ly6G(+)中性粒细胞与经肿瘤坏死因子-α预处理的间充质基质细胞（TNF-MSCs）共培养后，获得免疫抑制功能，可在体外抑制T细胞增殖，并在体内促进4T1肿瘤进展。此外，与TNF-MSCs共培养后，中性粒细胞中的精氨酸酶活性以及诱导型一氧化氮合酶、血清淀粉样蛋白A3、一些细胞因子和趋化因子及其受体的表达上调。抑制诱导型一氧化氮合酶活性可减弱TNF-MSC预共培养的中性粒细胞对T细胞增殖的抑制作用。
结论
间充质基质细胞将中性粒细胞编程为具有免疫抑制和促进肿瘤作用的表型。
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