Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β1
Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β1
复制标题
癌症扩增的骨髓源性抑制细胞通过膜结合 TGF-β1 诱导 NK 细胞无反应。
DOI：
10.4049/jimmunol.182.1.240
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发表时间：
2009-01-01
影响因子：
4.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Li, Hequan;Han, Yanmei;Cao, Xuetao
NK细胞是天然免疫的重要效应者，在抗肿瘤免疫中发挥着重要作用。髓源性抑制细胞(MDSC)是一类CD11b(+)Gr-1(+)髓系细胞，在肿瘤进展过程中急剧扩张，可抑制T细胞和树突状细胞，有助于肿瘤免疫逃逸。然而，MDSC对荷瘤宿主NK细胞天然功能的调节仍需进一步研究。在本研究中，我们发现在所有的荷瘤模型中，肝和脾的NK细胞的功能都明显受损，表明肿瘤对肝脏NK细胞功能的损害是一个普遍的现象。然后制备原位荷瘤小鼠作为肿瘤模型，研究肝脏NK细胞的损伤情况。我们发现NK细胞功能的下调与肝和脾中MDSC的显著增加呈负相关。MDSC在体外和体内均能抑制NK细胞的细胞毒作用、NKG2D表达和干扰素-γ的产生。与MDSC共同孵育后，NK细胞不能被激活产生干扰素-γ。此外，MDSC膜上结合的转化生长因子-β1参与了MDSC对NK细胞的抑制作用。原位肝癌小鼠肝NK细胞受损的功能可通过去除MDSC而恢复，但不能恢复调节性T细胞。因此，肿瘤扩增的MDSC可以通过膜结合的转化生长因子-β1诱导NK细胞无能。在荷瘤宿主中，MDSC是肝脏NK细胞功能的主要负调节细胞，而不是调节性T细胞。我们的研究为肿瘤免疫逃逸提供了新的机制解释。免疫学杂志，2009,182：240-249。
NK cells, the important effector of innate immunity, play critical roles in the antitumor immunity. Myeloid-derived suppressor cells (MDSC), a population of CD11b(+)Gr-1(+) myeloid cells expanded dramatically during tumor progression, can inhibit T cells and dendritic cells, contributing to tumor immune escaper. However, regulation of NK cell innate function by MDSC in tumor-bearing host needs to be investigated. In this study, we found that the function of NK cells from liver and spleen was impaired significantly in all tumor-bearing models, indicating the impairment of hepatic NK cell function by tumor is a universal phenomenon. Then we prepared the orthotopic liver cancer-bearing mice as tumor model to investigate how hepatic NK cells are impaired. We show that down-regulation of NK cell function is inversely correlated with the marked increase of MDSC in liver and spleen. MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. After incubation with MDSC, NK cells could not be activated to produce IFN-gamma. Furthermore, membrane-bound TGF-beta 1 on MDSC is responsible for MDSC-mediated suppression of NK cells. The impaired function of hepatic NK cells in orthotopic liver cancer-bearing mice could be restored by depletion of MDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC can induce anergy of NK cells via membrane-bound TGF-beta 1. MDSC, but not regulatory T cells, are main negative regulator of hepatic NK cell function in tumor-bearing host. Our study provides new mechanistic explanations for tumor immune escape. The Journal of Immunology, 2009, 182: 240-249.