Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer.
Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer.
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DOI：
10.1080/2162402x.2015.1062968
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发表时间：
2016-04
期刊：
影响因子：
7.2
通讯作者：
Chouaib S
中科院分区：
文献类型：
--
作者：
Berchem G;Noman MZ;Bosseler M;Paggetti J;Baconnais S;Le Cam E;Nanbakhsh A;Moussay E;Mami-Chouaib F;Janji B;Chouaib S
肿瘤源性微泡（TD-MV）是癌细胞释放的关键介质，可以使肿瘤微环境中的相邻细胞敏感。TD-MV是由外来体和MV组成的细胞外囊泡，并促进癌症侵袭和转移。肿瘤内缺氧是所有实体瘤的组成部分。低氧肿瘤脱落MV和NK介导的细胞毒性之间的关系仍然未知。在本文中，我们报道了来自缺氧肿瘤细胞的MV与来自常氧肿瘤细胞的MV在性质上不同。使用多种肿瘤模型，我们表明，低氧MV抑制更多的NK细胞功能相比，常氧MV。低免疫力TD-MV包装两种免疫抑制因子，其参与体外和体内针对不同肿瘤细胞的自然杀伤（NK）细胞毒性的损害。我们发现，在它们被NK细胞摄取后，低氧TD-MV将TGF-β1转移到NK细胞，降低活化受体NKG 2D的细胞表面表达，从而抑制NK细胞功能。microRNA分析显示，在低氧TD-MV中存在高水平的miR-210和miR-23 a。我们证明了低氧TD-MV中的miR-23 a作为额外的免疫抑制因子起作用，因为它直接靶向NK细胞中CD 107 a的表达。据我们所知，这是第一个研究表明，低氧肿瘤细胞分泌MV可以教育NK细胞，降低其抗肿瘤免疫反应。这项研究强调了一种新的免疫抑制机制介导的缺氧TD-MV的存在，并进一步提高了我们对缺氧肿瘤微环境中普遍存在的免疫抑制机制的理解。
Tumor-derived microvesicles (TD-MVs) are key mediators which are shed by cancer cells and can sensitize neighboring cells in the tumor microenvironment. TD-MVs are extracellular vesicles composed of exosomes and MVs and promote cancer invasion and metastasis. Intratumoral hypoxia is an integral component of all solid tumors. The relationship between hypoxic tumor-shed MVs and NK-mediated cytotoxicity remains unknown. In this paper, we reported that MVs derived from hypoxic tumor cells qualitatively differ from those derived from normoxic tumor cells. Using multiple tumor models, we showed that hypoxic MVs inhibit more NK cell function as compared to normoxic MVs. Hypoxic TD-MVs package two immunosuppressive factors involved in the impairment of natural killer (NK) cell cytotoxicity against different tumor cells in vitro and in vivo. We showed that following their uptake by NK cells, hypoxic TD-MVs transfer TGF-β1 to NK cells, decreasing the cell surface expression of the activating receptor NKG2D, thereby inhibiting NK cell function. MicroRNA profiling revealed the presence of high levels of miR-210 and miR-23a in hypoxic TD-MVs. We demonstrated that miR-23a in hypoxic TD-MVs operates as an additional immunomosuppressive factor, since it directly targets the expression of CD107a in NK cells. To our knowledge, this is the first study to show that hypoxic tumor cells by secreting MVs can educate NK cells and decrease their antitumor immune response. This study highlights the existence of a novel mechanism of immune suppression mediated by hypoxic TD-MVs and further improves our understanding of the immunosuppressive mechanisms prevailing in the hypoxic tumor microenvironment.