Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients
Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients
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DOI：
10.4049/jimmunol.172.12.7335
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发表时间：
2004-06-15
影响因子：
4.4
通讯作者：
Heo, DS
中科院分区：
文献类型：
--
作者：
Lee, JC;Lee, KM;Heo, DS
癌症患者的自然杀伤（NK）细胞功能严重受损，但其潜在的受损机制尚未明确。在本研究中，我们有证据表明肿瘤分泌的转化生长因子-β1（TGF -β1）通过下调一种NK激活受体NKG2D，导致NK细胞裂解活性降低。与正常志愿者相比，人类肺癌或结直肠癌患者血浆中TGF -β1水平升高，且这种升高与这些患者NK细胞上NKG2D的表面表达呈负相关。将NK细胞与来自癌症患者的血浆一起孵育，会特异性地下调NKG2D的表面表达，而加入中和性抗TGF -β1单克隆抗体则完全恢复了NKG2D的表面表达。同样，将NK细胞和淋巴因子激活的杀伤细胞与TGF -β1一起孵育，会导致与NK细胞毒性受损相关的NKG2D表面表达显著降低。TGF -β1对NKG2D的调节是特异性的，因为其他NK受体（如CD94/NKG2A、CD44、CD16、2B4或CD56）的表达不受TGF -β1影响。TGF -β1导致的NK细胞毒性受损并非由于裂解成分（如穿孔素或Fas）或凋亡途径的改变，而似乎是由于缺乏NKG2D表达。综上所述，我们的数据表明，癌症患者NK功能受损可归因于TGF -β1的分泌导致激活受体（如NKG2D）的下调。
NK cell function in cancer patients is severely impaired, but the mechanism underlying this impairment is not clearly understood. In this study we show evidence that TGF-beta1 secreted by tumors is responsible for the poor NK lytic activity via down-regulating an NK-activating receptor, NKG2D. The plasma level of TGF-beta1 in human lung cancer or colorectal cancer patients was elevated compared with that in normal volunteers, and this elevation was inversely correlated with surface expression of NKG2D on NK cells in these patients. Incubation of NK cells with plasma obtained from cancer patients specifically down-modulated surface NKG2D expression, whereas addition of neutralizing anti-TGF-beta1 mAbs completely restored surface NKG2D expression. Likewise, incubation of NK cells and lymphokine-activated killer cells with TGF-beta1 resulted in dramatic reduction of surface NKG2D expression associated with impaired NK cytotoxicity. Modulation of NKG2D by TGF-beta1 was specific, as expression of other NK receptors, CD94/NKG2A, CD44, CD16, 2B4, or CD56, was not affected by TGF-beta1. Impaired NK cytotoxicity by TGF-beta1 was not due to alteration of lytic moieties, such as perforin or Fas, or apoptotic pathway, but, rather, appeared to be due to lack of NKG2D expression. Taken together, our data suggest that impaired NK function in cancer patients can be attributed to down-modulation of activating receptors, such as NKG2D, via secretion of TGF-beta1.