Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction.
Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction.
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DOI：
10.1186/1471-2407-14-738
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发表时间：
2014-10-02
期刊：
影响因子：
3.8
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Peng YP;Zhang JJ;Liang WB;Tu M;Lu ZP;Wei JS;Jiang KR;Gao WT;Wu JL;Xu ZK;Miao Y;Zhu Y
自然杀伤（NK）细胞在包括胰腺癌在内的不同癌症的非特异性免疫应答中发挥关键作用。然而，NK细胞的抗肿瘤作用在胰腺癌进展期间降低。NK细胞促进肿瘤免疫逃逸的调节途径尚不清楚，因此我们的目的是研究促成因素的作用。从新鲜健康人外周血中分离NK细胞，与正常人胰腺导管细胞hTERT-HPNE、人胰腺癌细胞系SW 1990和BxPc-3共培养。采用流式细胞仪检测NK细胞表面受体和细胞毒颗粒的表达，NK细胞凋亡和细胞毒活性，酶联免疫吸附试验检测细胞因子的表达。RT-PCR检测hTERT-HPNE和SW 1990细胞中MMP-9、IDO和考克斯-2的表达水平。使用SPSS 19.0软件通过独立t检验确定数据组之间的统计学差异。我们的研究结果表明，与正常胰腺细胞相比，暴露于胰腺癌细胞后NK细胞功能显著下调，表现为活化表面受体（NKG 2D、DNAM-1、NKp 30和NKp 46）和细胞毒性颗粒（穿孔素和颗粒酶B）表达降低;细胞因子（TNF-α和IFN-γ）分泌减少;以及对髓性白血病K562细胞的细胞毒性降低。进一步的研究表明，MMP-9和IDO可能通过促进肿瘤免疫逃避而参与SW 1990细胞诱导的NK细胞功能障碍。TIMP-1和/或1-MT阻断可部分恢复NK功能。总之，胰腺癌细胞诱导的MMP-9和IDO升高介导NK细胞功能障碍。我们的研究结果可能有助于胰腺癌患者基于NK细胞的免疫治疗的发展。
Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti-tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors. NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software. Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α and IFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function. Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer.
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