Leucine-tRNA-synthetase-2-expressing B cells contribute to colorectal cancer immunoevasion

• DOI: 10.1016/j.immuni.2022.04.017
• Publication Date: 2022-06-03T14:44:30Z
• Authors: Zhiqiang Wang; Zhou Lu; Shengli Lin; Jie Xia; Ziwen Zhong; Zhangjuan Xie; Yun Xing; Jingbo Qie; Mengxia Jiao; Yifan Li; Haoyu Wen; Pengyuan Zhao; Dan Zhang; Pinghong Zhou; Jiawen Qian; Feifei Luo; Luman Wang; Hongxiu Yu; Jie Liu; Jie Gu; Ronghua Liu; Yiwei Chu
• Keywords: Amino Acyl-tRNA Synthetases; Mice; RNA, Transfer; Leucine; Animals; Humans; Colorectal Neoplasms; NAD; Mitochondria; 3. Good health

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.