Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis
Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis
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DOI：
10.1172/jci69369
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发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Wu, Jennifer D.
中科院分区：
文献类型：
--
作者：
Liu, Gang;Lu, Shengjun;Wu, Jennifer D.
激活型受体NK细胞群2成员D（NKG2D）在实验动物模型中介导抗肿瘤免疫。然而，NKG2D配体在临床上是促进肿瘤抑制还是肿瘤进展仍存在争议。在此，我们描述了两种新型的“人源化”双转基因（bi - Tg）小鼠品系，在自发性肿瘤发生的小鼠前列腺转基因腺癌（TRAMP）模型中，天然人NKG2D配体MHC I类多肽相关序列B（MICB）或改造的膜限制性MICB（MICB.A2）在前列腺中表达。双转基因TRAMP/MICB小鼠进展期癌和转移的发生率显著增加，而TRAMP/MICB.A2小鼠因持续的NKG2D介导的抗肿瘤免疫而获得长期无瘤生存。从机制上讲，我们发现TRAMP/MICB小鼠的癌症进展与外周NK细胞群的缺失有关，这是由于肿瘤来源的可溶性MICB（sMICB）血清水平较高。前列腺癌患者也表现出外周NK细胞减少和sMIC水平升高。我们的研究不仅在“人源化”小鼠模型中提供了直接证据，表明可溶性和膜限制性NKG2D配体对癌症进展具有相反的影响，还揭示了sMIC诱导的NK细胞抗肿瘤免疫受损的机制。我们的研究结果表明，在基于NK细胞的癌症免疫治疗中应考虑可溶性NKG2D配体的影响，并且我们独特的小鼠模型对治疗优化应该是有价值的。
The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligand.s contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic ad.enocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligand.s should be considered in NK cell-based cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization.