Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling
Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling
复制标题
肿瘤微环境中的乳酸通过干扰 mTOR 信号传导导致 NKT 细胞功能障碍
DOI：
10.1007/s11427-016-0348-7
复制
发表时间：
2016-12-01
影响因子：
9.1
通讯作者：
Bai, Li
中科院分区：
文献类型：
--
作者：
Xie, Di;Zhu, Shasha;Bai, Li
细胞代谢已显示调节免疫细胞的分化和功能。肿瘤相关免疫细胞由于肿瘤微环境中细胞代谢的改变而发生表型和功能的改变。NKT细胞是针对肿瘤的免疫疗法的良好候选者，并已用于几项临床试验。然而，肿瘤微环境对NKT细胞功能的影响仍不清楚。在我们的研究中，肿瘤微环境中的乳酸抑制NKT细胞产生IFNγ和IL 4，并且观察到对IFNγ的更深刻的影响。通过调节培养液的pH值，我们进一步发现，低细胞外pH值可以简单地诱导NKT细胞功能障碍。此外，低细胞外pH值通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号传导和早幼粒细胞白血病锌指蛋白（PLZF）核转位抑制NKT细胞功能。总之，我们的研究结果表明，肿瘤酸性微环境可以通过代谢控制干扰NKT细胞功能。
Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells, and more profound influence on IFNγ was observed. By adjusting the pH of culture medium we further showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin (mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger (PLZF). Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.