Obstructing shedding of the immunostimulatory MHC class I chain-related gene B prevents tumor formation.
Obstructing shedding of the immunostimulatory MHC class I chain-related gene B prevents tumor formation.
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DOI：
10.1158/1078-0432.ccr-08-1305
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发表时间：
2009-01-15
期刊：
影响因子：
--
通讯作者：
Plymate SR
中科院分区：
文献类型：
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作者：
Wu JD;Atteridge CL;Wang X;Seya T;Plymate SR
临床观察表明，MHC I类链相关分子（MIC）的脱落可能是肿瘤逃避宿主免疫监视和进展的机制之一。然而，这一假设从未得到证实。在本研究中，我们使用前列腺肿瘤模型验证了这一假设，并研究了MIC脱落对肿瘤发展的影响。我们生成了一种抗脱落不可切割的MICB （MICB. a2）。我们过度表达MICB。A2、野生型MICB和重组可溶性MICB （rsMICB）在小鼠前列腺肿瘤TRAMP-C2 （TC2）细胞中的表达，并将这些细胞植入严重联合免疫缺陷（SCID）小鼠体内。植入TC2-MICB的动物未出现肿瘤。A2细胞;而所有被植入TC2、TC2- micb或TC2- rsmicb细胞的动物都出现了肿瘤。当肿瘤植入前给动物注射nkg2d特异性抗体CX5或纯化的rsMICB时，所有植入TC2-MICB的动物。A2细胞发生肿瘤。体外细胞毒性实验显示，nkg2d介导的NK细胞功能在这些预先攻击的动物中丧失，这表明血清中持续水平的可溶性MICB会损害NK细胞功能，从而允许肿瘤生长。这些数据表明，MIC脱落可能对转化细胞的肿瘤形成有重要作用，抑制MIC脱落以维持NKG2D受体-MIC配体识别可能在靶向癌症治疗中具有潜在的临床意义。
Clinical observations have suggested that shedding of the MHC class I chain-related molecule (MIC) may be one of the mechanisms by which tumors evade host immune surveillance and progress. However, this hypothesis has never been proven. In this study, we tested this hypothesis using a prostate tumor model and investigated the impact of shedding of MIC on tumor development. We generated a shedding-resistant non-cleavable form of MICB (MICB.A2). We overexpressed MICB.A2, the wild-type MICB, and the recombinant soluble MICB (rsMICB) in mouse prostate tumor TRAMP-C2 (TC2) cells and implanted these cells into severe combined immunodeficiency (SCID) mice. No tumors were developed in animals that were implanted with TC2-MICB.A2 cells; whereas all the animals that were implanted with TC2, TC2-MICB, or TC2-rsMICB cells developed tumors. When a NKG2D-specific antibody CX5 or purified rsMICB was administrated to animals prior to tumor implantation, all animals that were implanted with TC2-MICB.A2 cells developed tumors. In vitro cytotoxicity assay revealed the loss of NKG2D-mediated NK cell function in these pre-challenged animals suggesting that persistent levels of soluble MICB in the serum can impair NK cell function and thus allow tumor growth. These data suggest that MIC shedding may contribute significantly to tumor formation by transformed cells and that inhibition of MIC shedding to sustain the NKG2D receptor-MIC ligand recognition may have potential clinical implication in targeted cancer treatment.