肿瘤微环境中的乳酸通过干扰 mTOR 信号导致 NKT 细胞功能障碍。
Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling.
机构信息
CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.
Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China.
出版信息
Sci China Life Sci. 2016 Dec;59(12):1290-1296. doi: 10.1007/s11427-016-0348-7. Epub 2016 Dec 5.
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.
细胞代谢已被证明可调节免疫细胞的分化和功能。由于肿瘤微环境中细胞代谢的变化，肿瘤相关免疫细胞发生表型和功能改变。NKT 细胞是抗肿瘤免疫疗法的良好候选者，已在几项临床试验中得到应用。然而，肿瘤微环境对 NKT 细胞功能的影响尚不清楚。在我们的研究中，肿瘤微环境中的乳酸抑制了 NKT 细胞产生 IFNγ 和 IL4，并且对 IFNγ 的影响更为明显。通过调整培养基的 pH 值，我们进一步表明，NKT 细胞的功能障碍可以简单地由细胞外 pH 值降低引起。此外，低细胞外 pH 值通过抑制雷帕霉素靶蛋白 (mTOR) 信号和早幼粒细胞白血病锌指 (PLZF) 的核易位来抑制 NKT 细胞功能。总之，我们的结果表明，肿瘤酸性微环境可以通过代谢控制来干扰 NKT 细胞的功能。
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