Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function
Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function
复制标题
DOI：
10.4049/jimmunol.176.3.1375
复制
发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Zhang, HG
中科院分区：
文献类型：
--
作者：
Liu, CR;Yu, SH;Zhang, HG
许多肿瘤细胞会脱落称为外泌体的特殊膜囊泡。在这项研究中，我们发现用 TS/A 或 4T.1 鼠乳腺肿瘤细胞产生的外泌体预处理小鼠，可导致同基因 BALB/c 小鼠和裸鼠中植入的肿瘤细胞加速生长。由于植入的 TS/A 肿瘤细胞在 NK 细胞耗尽的小鼠中生长得更快，我们分析了肿瘤来源的外泌体对 NK 细胞的影响。铬释放测定证明，肿瘤来源的外泌体在离体和体外抑制 NK 细胞的细胞毒活性。根据 FACS 分析确定，用 TS/A 肿瘤外泌体治疗小鼠的肺和脾中的 NK 细胞百分比也有所降低。 NK 细胞活性的关键特征受到抑制，包括穿孔素但颗粒酶 B 的释放，以及细胞周期蛋白 D3 的表达和 Jak3 介导途径的激活。人类肿瘤细胞系也被发现产生能够抑制 IL-2 刺激的 NK 细胞增殖的外泌体。树突状细胞或 B 细胞产生的外泌体则没有。外泌体呈递肿瘤抗原正在被考虑作为一种癌症疫苗策略；然而，我们发现用肿瘤外泌体预处理小鼠会削弱用肿瘤外泌体离体脉冲的同基因树突状细胞的保护作用。我们认为肿瘤外泌体通过阻断 IL-2 介导的 NK 细胞激活及其对肿瘤细胞的细胞毒性反应来促进肿瘤的生长。
Many tumor cells shed specialized membrane vesicles known as exosomes. In this study, we show that pretreatment of mice with exosomes produced by TS/A or 4T.1 murine mammary tumor cells resulted in accelerated growth of implanted tumor cells in both syngeneic BALB/c mice and nude mice. As implanted TS/A tumor cells grew more rapidly in mice that had been depleted of NK cells, we analyzed the effects of the tumor-derived exosomes on NK cells. The tumor-derived exosomes inhibit NK cell cytotoxic activity ex vivo and in vitro as demonstrated by chromium release assays. The treatment of mice with TS/A tumor exosomes also led to a reduction in the percentages of NK cells, as determined by FACS analysis, in the lungs and spleens. Key features of NK cell activity were inhibited, including release of perforin but not granzyme B, as well as the expression of cyclin D3 and activation of the Jak3-mediated pathways. Human tumor cell lines also were found to produce exosomes that were capable of inhibiting IL-2-stimulated NK cell proliferation. Exosomes produced by dendritic cells or B cells did not. The presentation of tumor Ags by exosomes is under consideration as a cancer vaccine strategy; however, we found that pretreatment of mice with tumor exosomes blunted the protective effect of syngeneic dendritic cells pulsed ex vivo with tumor exosomes. We propose that tumor exosomes contribute to the growth of tumors by blocking IL-2-mediated activation of NK cells and their cytotoxic response to tumor cells.