Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer.
Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer.
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DOI：
10.1172/jci22206
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发表时间：
2004-08
期刊：
影响因子：
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通讯作者：
Jennifer D. Wu;L. M. Higgins;A. Steinle;D. Cosman;K. Haugk;S. Plymate
中科院分区：
文献类型：
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作者：
Jennifer D. Wu;L. M. Higgins;A. Steinle;D. Cosman;K. Haugk;S. Plymate
MHC I类链相关分子（MIC）先前已显示在大多数上皮肿瘤细胞上被诱导。活化免疫受体NKG 2D与MIC的结合触发NK细胞并增强抗原特异性CTL抗肿瘤免疫。MIC-NKG 2D系统被提议参与上皮肿瘤免疫监视。有趣的是，研究表明，肿瘤可能通过MIC脱落诱导的效应细胞功能受损来逃避MIC-NKG 2D介导的免疫。在这里，我们证明了我们所知的第一个证据，即MIC脱落和NK细胞功能缺陷与前列腺癌的疾病分级显著相关。MIC在前列腺癌中广泛表达。然而，表面靶MIC的存在被脱落抵消。晚期癌症患者血清可溶性MIC（sMIC）水平显著升高，NK细胞功能缺乏。最后，NK细胞功能的缺陷可以通过在体外用IL-2或IL-15治疗来克服。我们的研究结果表明，（a）MIC-NKG 2D免疫监视缺陷可能导致前列腺癌进展，（B）sMIC可能是前列腺癌的一种新型生物标志物，（c）在基于细胞的适应性免疫治疗中，使用细胞因子恢复MIC-NKG 2D介导的免疫可能对前列腺癌具有临床意义。
The MHC class I chain-related molecules (MICs) have previously been shown to be induced on most epithelial tumor cells. Engagement of MIC by the activating immune receptor NKG2D triggers NK cells and augments antigen-specific CTL anti-tumor immunity. The MIC-NKG2D system was proposed to participate in epithelial tumor immune surveillance. Paradoxically, studies suggest that tumors may evade MIC-NKG2D-mediated immunity by MIC shedding-induced impairment of effector cell function. Here we demonstrate the first evidence to our knowledge of a significant correlation of MIC shedding and deficiency in NK cell function with the grade of disease in prostate cancer. MIC is widely expressed in prostate carcinoma. The presence of surface target MIC, however, is counteracted by shedding. A significant increase in serum levels of soluble MIC (sMIC) and deficiency in NK cell function was shown in patients with advanced cancer. Finally, the deficiency in NK cell function can be overcome by treatment with IL-2 or IL-15 in vitro. Our results suggest that (a) deficiency in MIC-NKG2D immune surveillance may contribute to prostate cancer progression, (b) sMIC may be a novel biomarker for prostate cancer, and (c) using cytokines to restore MIC-NKG2D-mediated immunity may have clinical significance for prostate cancer in cell-based adaptive immunotherapy.