Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Liver Cancer Institute, Department of Anesthesiology, Zhongshan Hospital, Shanghai 200032, China.
Immunity. 2022 Jun 14;55(6):1067-1081.e8. doi: 10.1016/j.immuni.2022.04.017. Epub 2022 Jun 3.
Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-β1 (TGF-β1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.
免疫调节 B 细胞通过未知的特征和机制阻碍抗肿瘤免疫。我们报告了在小鼠和人类进展性结直肠癌 (CRC) 中存在亮氨酰-tRNA 合成酶-2 (LARS2) 表达的 B 细胞亚群 (LARS B)，其具有转化生长因子-β1 (TGF-β1) 优势调控特征。值得注意的是，LARS B 细胞表现出亮氨酸营养偏好，并表现出活跃的线粒体氨基酸酰-tRNA 生物合成。它们位于三级淋巴结构之外，与结直肠增生和 CRC 患者生存时间缩短相关。亮氨酸饮食诱导 LARS B 细胞的产生，而通过 Lars2 基因敲除或亮氨酸阻断消除 LARS B 细胞则抑制 CRC 的免疫逃逸。在机制上，LARS2 程序性调节烟酰胺腺嘌呤二核苷酸 (NAD) 的再生和氧化代谢，从而决定了 LARS B 细胞的调节特征，其中涉及 NAD 依赖性蛋白去乙酰化酶 SIRT1。我们提出了一种亮氨酸饮食方案来抑制 LARS B 细胞，这对 CRC 治疗是安全且有效的。
