Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells.
Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells.
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DOI：
10.4049/jimmunol.1000901
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发表时间：
2010-08-15
期刊：
影响因子：
--
通讯作者：
Epstein AL
中科院分区：
文献类型：
--
作者：
Lechner MG;Liebertz DJ;Epstein AL
肿瘤免疫耐受可源于抑制性细胞群的募集，包括髓源性抑制细胞（MDSC）。在癌症患者中，MDSC增多与疾病更具侵袭性及预后不良相关。
通过逆转录聚合酶链反应（RT - PCR）评估了MDSC诱导性人类实体肿瘤细胞系对15种免疫因子（转化生长因子β、白细胞介素 - 1β、白细胞介素 - 4、白细胞介素 - 6、白细胞介素 - 10、粒细胞 - 巨噬细胞集落刺激因子、巨噬细胞集落刺激因子、吲哚胺2,3 - 双加氧酶、FMS样酪氨酸激酶3配体、干细胞因子、诱导型一氧化氮合酶、精氨酸酶 - 1、肿瘤坏死因子α、环氧化酶2、血管内皮生长因子）的表达。基于这些数据，然后通过测量其在CD3/CD28刺激后抑制新鲜自体人T细胞增殖以及干扰素γ产生的能力，在体外测试细胞因子混合物从健康供体外周血单个核细胞（PBMC）产生抑制性CD33⁺细胞的能力。对诱导产生的MDSC从形态、表面表型和基因表达谱方面进行了特征描述。
MDSC诱导性癌细胞系展示了多种产生MDSC的途径，包括白细胞介素 - 6、白细胞介素 - 1β、环氧化酶2、巨噬细胞集落刺激因子和吲哚胺2,3 - 双加氧酶的过度表达。粒细胞 - 巨噬细胞集落刺激因子和白细胞介素 - 6在体外最能产生具有强大抑制能力的CD33⁺细胞，其次是粒细胞 - 巨噬细胞集落刺激因子 + 白细胞介素 - 1β、前列腺素E2、肿瘤坏死因子α或血管内皮生长因子。对细胞因子诱导的抑制性细胞的特征研究显示，这些细胞为CD33⁺CD11b⁺CD66b⁺人类白细胞抗原 - DR低表达白细胞介素 - 13受体α2中等表达的大单核细胞，具有丰富的嗜碱性细胞质。诱导型一氧化氮合酶、转化生长因子β、NADPH氧化酶2、血管内皮生长因子和/或精氨酸酶 - 1的表达也上调，并且Transwell实验表明对自体T细胞的抑制是接触依赖性的。
由粒细胞 - 巨噬细胞集落刺激因子和白细胞介素 - 6从外周血单个核细胞产生的抑制性CD33⁺细胞与人MDSC一致。这项研究表明，这些细胞因子是抑制癌症患者中MDSC诱导的潜在治疗靶点。
Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSC). In cancer patients, increased MDSC correlate with more aggressive disease and a poor prognosis. Expression of 15 immune factors (TGFβ, IL-1β, IL-4, IL-6, IL-10, GM-CSF, M-CSF, IDO, FLT3L, c-kit L, iNOS, ARG-1, TNFα, COX2, VEGF) by MDSC-inducing human solid tumor cell lines was evaluated by RT-PCR. Based upon these data, cytokine mixtures were then tested for their ability to generate suppressive CD33+ cells from healthy donor PBMC in vitro by measuring their ability to inhibit the proliferation of, and IFNγ production by, fresh autologous human T cells after CD3/CD28 stimulation. Induced MDSC were characterized with respect to their morphology, surface phenotype, and gene expression profile. MDSC-inducing cancer cell lines demonstrated multiple pathways for MDSC generation, including over-expression of IL-6, IL-1β, COX2, M-CSF, and IDO. CD33+ cells with potent suppressive capacity were best generated in vitro by GM-CSF and IL-6, and secondarily by GM-CSF + IL-1β, PGE2, TNFα, or VEGF. Characterization studies of cytokine-induced suppressive cells revealed CD33+CD11b+CD66b+HLA-DRlowIL-13Rα2int large mononuclear cells with abundant basophilic cytoplasm. Expression of iNOS, TGFβ, NOX2, VEGF, and/or ARG-1 was also up-regulated and transwell studies showed suppression of autologous T cells to be contact dependent. Suppressive CD33+ cells generated from PBMC by GM-CSF and IL-6 were consistent with human MDSC. This study suggests that these cytokines are potential therapeutic targets for the inhibition of MDSC induction in cancer patients.
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影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
11.2
作者：
Sinha, Pratima;Clements, Virginia K.;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
影响因子：
9
作者：
Morse, MA;Zhou, LJ;Smith, C
通讯作者：
Smith, C
影响因子：
11.2
作者：
Rodriguez PC;Ernstoff MS;Hernandez C;Atkins M;Zabaleta J;Sierra R;Ochoa AC
通讯作者：
Ochoa AC
影响因子：
8.6
作者：
Liu, Yu;Zeng, Bin;Yang, Rongcun
通讯作者：
Yang, Rongcun