Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Cell Metab. 2018 Jan 9;27(1):85-100.e8. doi: 10.1016/j.cmet.2017.10.006. Epub 2017 Nov 9.
Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD axis could increase the efficacy of anti-tumor adoptive T cell therapy.
高度活跃的效应功能和持久的存在性，分别是 Th1 和 Th17 细胞的关键属性，是具有强大抗肿瘤 T 细胞的关键特征。在这里，我们建立了体外培养条件来产生混合 Th1/17 细胞，这些细胞在体内长期存在，同时保持其效应功能。通过转录组学和代谢谱分析方法，我们表明 Th1/17 细胞增强的抗肿瘤特性依赖于组蛋白去乙酰化酶 Sirt1 的 NAD 依赖性活性增加。Sirt1 活性的药理学或遗传抑制削弱了 Th1/17 细胞的抗肿瘤潜力。重要的是，具有降低的 NAD 酶 CD38 表面表达的 T 细胞表现出内在更高的 NAD、增强的氧化磷酸化、更高的谷氨酰胺分解代谢和改变的线粒体动力学，从而极大地改善了肿瘤控制。最后，即使使用 Th0 抗肿瘤 T 细胞，阻断 CD38 表达也能改善肿瘤控制。因此，靶向 CD38-NAD 轴的策略可以提高抗肿瘤过继性 T 细胞疗法的疗效。
