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 establishedex vivoculture conditions to generate hybrid Th1/17 cells, which persisted long-termin vivowhile 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.

中文翻译：

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CD38-NAD +轴调节免疫治疗抗肿瘤T细胞反应。

增强的效应子功能和持久的持久性分别是Th1和Th17细胞的关键属性，是有效的抗肿瘤T细胞的关键特征。在这里，我们建立了体外培养条件，以产生杂交的Th1 / 17细胞，该细胞在体内长期维持，同时保持其效应子功能。使用转录组学和代谢谱分析方法，我们显示Th1 / 17细胞增强的抗肿瘤特性取决于组蛋白脱乙酰基酶Sirt1的NAD +依赖性活性的增加。Sirt1活性的药理或遗传抑制削弱了Th1 / 17细胞的抗肿瘤潜力。重要的是，NADase CD38表面表达降低的T细胞在本质上表现出更高的NAD +，增强的氧化磷酸化，更高的谷氨酰胺分解，并改变了线粒体动力学，从而大大改善了肿瘤的控制。最后，即使使用Th0抗肿瘤T细胞，阻断CD38的表达仍可改善肿瘤控制。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。