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Abstract：
Although tumor-infiltrating lymphocytes (TILs) maintain their ability to proliferate, persist, and eradicate tumors, they are frequently dysfunctional in situ. By performing both whole-genome CRISPR and metabolic inhibitor screens, we identify that nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. NAMPT is low in TILs, and its expression is controlled by the transcriptional factor Tubby (TUB), whose activity depends on the T cell receptor-phospholipase C gamma (TCR-PLCγ) signaling axis. The intracellular level of NAD+, whose synthesis is dependent on the NAMPT-mediated salvage pathway, is also decreased in TILs. Liquid chromatography-mass spectrometry (LC-MS) and isotopic labeling studies confirm that NAD+ depletion led to suppressed glycolysis, disrupted mitochondrial function, and dampened ATP synthesis. Excitingly, both adoptive CAR-T and anti-PD1 immune checkpoint blockade mouse models demonstrate that NAD+ supplementation enhanced the tumor-killing efficacy of T cells. Collectively, this study reveals that an impaired TCR-TUB-NAMPT-NAD+ axis leads to T cell dysfunction in the tumor microenvironment, and an over-the-counter nutrient supplement of NAD+ could boost T-cell-based immunotherapy.
摘要：
尽管肿瘤浸润淋巴细胞（TIL）保持其增殖能力，坚持,根除肿瘤，它们经常在原地功能失调。通过进行全基因组CRISPR和代谢抑制剂筛选，我们确定烟酰胺磷酸核糖基转移酶（NAMPT）是T细胞活化所必需的。TIL的NAMPT很低，其表达受转录因子Tubby（TUB）控制，其活性取决于T细胞受体-磷脂酶Cγ（TCR-PLCγ）信号轴。NAD+的细胞内水平，其合成依赖于NAMPT介导的救助途径，在TIL中也有所下降。液相色谱-质谱（LC-MS）和同位素标记研究证实，NAD消耗导致糖酵解受到抑制，线粒体功能中断，抑制ATP合成。令人兴奋的是,过继CAR-T和抗PD1免疫检查点阻断小鼠模型均表明,NAD+补充剂可增强T细胞的肿瘤杀伤功效.总的来说，这项研究表明，受损的TCR-TUB-NAMPT-NAD+轴导致肿瘤微环境中的T细胞功能障碍，非处方营养补充NAD+可以促进基于T细胞的免疫疗法。
