Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.
Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.
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DOI：
10.1371/journal.pone.0108925
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wikström P
中科院分区：
文献类型：
--
作者：
Lundholm M;Schröder M;Nagaeva O;Baranov V;Widmark A;Mincheva-Nilsson L;Wikström P
肿瘤来源的外泌体是一种纳米大小的内体起源的细胞外囊泡，已经成为肿瘤免疫逃避的促进因子，但它们在前列腺癌（PC）进展中的作用尚不清楚。在这项研究中，我们研究了前列腺肿瘤来源的外泌体下调NKG2D在自然杀伤细胞（NK）和CD8+ T细胞上表达的能力。NKG2D是一种激活细胞毒性受体，其在癌症中的异常丢失在免疫抑制中起重要作用。利用流式细胞术，我们发现人类PC细胞产生的外泌体在其表面表达NKG2D的配体。表达NKG2D配体的前列腺肿瘤源性外泌体以剂量依赖的方式选择性诱导NKG2D对NK和CD8+ T细胞的下调，导致体外细胞毒性功能受损。与这些发现一致，与健康个体相比，去势抵抗性PC （CRPC）患者循环NK和CD8+ T细胞表面NKG2D表达显著降低。肿瘤来源的外泌体可能参与了这种NKG2D的下调，因为从CRPC患者的血清或血浆中分离的外泌体与健康淋巴细胞孵育可触发效应淋巴细胞中NKG2D表达的下调。这些数据表明前列腺肿瘤源性外泌体下调PC患者nkg2d介导的细胞毒性反应，从而促进免疫抑制和肿瘤逃逸。
Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.
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影响因子：
11.2
作者：
Ashiru O;Boutet P;Fernández-Messina L;Agüera-González S;Skepper JN;Valés-Gómez M;Reyburn HT
通讯作者：
Reyburn HT
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。
影响因子：
4.4
作者：
Li, Hequan;Han, Yanmei;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
4.4
作者：
Lee, JC;Lee, KM;Heo, DS
通讯作者：
Heo, DS
影响因子：
3.7
作者：
Hedlund M;Nagaeva O;Kargl D;Baranov V;Mincheva-Nilsson L
通讯作者：
Mincheva-Nilsson L
影响因子：
2.2
作者：
Lamparski, HG;Metha-Damani, A;Le Pecq, JB
通讯作者：
Le Pecq, JB