Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion
Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion
复制标题
表达亮氨酸-tRNA-合酶-2的B细胞有助于结直肠癌免疫逃避
DOI：
10.1016/j.immuni.2022.04.017
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发表时间：
2022-06-14
期刊：
影响因子：
32.4
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
--
作者：
Wang, Zhiqiang;Lu, Zhou;Chu, Yiwei
免疫调节性B细胞通过未知的特征和机制阻碍抗肿瘤免疫。我们报道了在小鼠和人类进展性结直肠癌（CRC）中存在表达亮氨酸- trna -合成酶-2 （LARS2）的B细胞（LARS B）亚群，其转化生长因子- β 1 （tgf - β 1）主导调节特征。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酰基- trna生物合成。它们位于三级淋巴结构之外，与结直肠癌患者的结肠增生和生存期缩短有关。亮氨酸饮食诱导LARS B细胞生成，而Lars2基因消融或亮氨酸阻断导致的LARS B细胞缺失抑制了结直肠癌的免疫逃逸。在机制上，LARS2编程线粒体烟酰胺腺嘌呤二核苷酸（NAD(+)）再生和氧化代谢，从而决定了NAD依赖性蛋白去乙酰化酶sirtuin-1 （SIRT1）参与的LARS B细胞的调控特征。我们提出了一种抑制LARS B细胞的亮氨酸节食方案，这是一种安全有效的CRC治疗方案。
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-beta 1 (TGF-beta 1)-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.