Dr. Yiwei Chu’s group reveals the new mechanism underlying colorectal cancer immunoevasion
Source：Yiwei Chu
2022-06-11
On 3rd June, 2022, the team of Prof. Yiwei Chu and Dr. Ronghua Liu from Fudan University published a research article titled “Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion” in Immunity. They focused on the features and regulatory function of tumor-infiltrating B lymphocytes, and deeply revealed the dietary and metabolic mechanism by which regulatory B cells (Bregs) acquire their characteristics.
B lymphocyte in tumor immunity is emerging as a research hotspot in recent years. In solid tumors, B cells not only play anti-tumor immune response, but also play tumor-promoting effect through immune regulation in tumor microenvironment. There are many gaps in the research on the latter. In this study, Chu et al. systematically analyzed tumor-infiltrating B cells at different stages of colorectal cancer (CRC) by single-cell RNA sequencing, and found a new B cell subset (LARS B) with high expression of leucine-tRNA-synthase-2 (LARS2). LARS B cells were scattered in tumor stroma outside TLS, and rarely existed in normal tissues, bone marrow, spleen and peripheral blood. LARS B cell enrichment was positively correlated with poor prognosis of CRC patients. The core molecular LARS2 of LARS B cell is mainly located in mitochondria, responsible for translation of mitochondrial gene, including mitochondrial respiratory chain complex I-V. Compared with other B cell subsets in CRC, mitochondrial metabolism of LARS B subset was enhanced, especially NAD+ regeneration. NAD+-dependent deacetylase SIRT1 enhanced its binding ability to the promoter region of Tgfb1 by deacetylating transcription factor PAX5, which promoted Tgfb1 transcription. LARS B cell not only had regulatory feature dominated by TGF-β1, but also had leucine preference. Based on it, the group proposed a leucine-dieting scheme (7 days as a cycle: 4 days of normal and 3 days of leucine-deficient), which significantly inhibited LARS B cell-mediated CRC immunoevasion and slowed tumor progression.
The significance of this study is to provide a detailed elucidation of the regulatory feature of LARS B cell and demonstrate that it is related to leucine preference and oxidative phosphorylation. It is worth noting that this study focuses on the relationship between diet and immune regulation，proposing a safe and effective leucine diet. By periodically controlling leucine intake to limit LARS B cell, mouse CRC is well controlled. This study provides a new basis for dietary intervention in immunity by understanding tumor-associated B cells.
Since 2008, Prof. Yiwei Chu’s group has studied Breg and published a series of papers in Breg phenotype, regulatory function and related mechanism，not only in autoimmune diseases but also in tumors. In this article, Dr. Zhiqiang Wang from Department of Immunology, Dr. Shengli Lin and Dr. Zhou Lu from Zhongshan hospital are the co-first author. Junior PI Ronghua Liu and Prof. Yiwei Chu from Shanghai Medical College Fudan University are co-corresponding authors of this paper. This study was supported by the National Science Foundation of China, the Shanghai Rising-Star Program, the National Science and Technology Major Project of China.
Link：https://doi.org/10.1016/j.immuni.2022.04.017
B lymphocyte in tumor immunity is emerging as a research hotspot in recent years. In solid tumors, B cells not only play anti-tumor immune response, but also play tumor-promoting effect through immune regulation in tumor microenvironment. There are many gaps in the research on the latter. In this study, Chu et al. systematically analyzed tumor-infiltrating B cells at different stages of colorectal cancer (CRC) by single-cell RNA sequencing, and found a new B cell subset (LARS B) with high expression of leucine-tRNA-synthase-2 (LARS2). LARS B cells were scattered in tumor stroma outside TLS, and rarely existed in normal tissues, bone marrow, spleen and peripheral blood. LARS B cell enrichment was positively correlated with poor prognosis of CRC patients. The core molecular LARS2 of LARS B cell is mainly located in mitochondria, responsible for translation of mitochondrial gene, including mitochondrial respiratory chain complex I-V. Compared with other B cell subsets in CRC, mitochondrial metabolism of LARS B subset was enhanced, especially NAD+ regeneration. NAD+-dependent deacetylase SIRT1 enhanced its binding ability to the promoter region of Tgfb1 by deacetylating transcription factor PAX5, which promoted Tgfb1 transcription. LARS B cell not only had regulatory feature dominated by TGF-β1, but also had leucine preference. Based on it, the group proposed a leucine-dieting scheme (7 days as a cycle: 4 days of normal and 3 days of leucine-deficient), which significantly inhibited LARS B cell-mediated CRC immunoevasion and slowed tumor progression.
Figure LARS B mediates colorectal cancer immunoevasion
The significance of this study is to provide a detailed elucidation of the regulatory feature of LARS B cell and demonstrate that it is related to leucine preference and oxidative phosphorylation. It is worth noting that this study focuses on the relationship between diet and immune regulation，proposing a safe and effective leucine diet. By periodically controlling leucine intake to limit LARS B cell, mouse CRC is well controlled. This study provides a new basis for dietary intervention in immunity by understanding tumor-associated B cells.
Since 2008, Prof. Yiwei Chu’s group has studied Breg and published a series of papers in Breg phenotype, regulatory function and related mechanism，not only in autoimmune diseases but also in tumors. In this article, Dr. Zhiqiang Wang from Department of Immunology, Dr. Shengli Lin and Dr. Zhou Lu from Zhongshan hospital are the co-first author. Junior PI Ronghua Liu and Prof. Yiwei Chu from Shanghai Medical College Fudan University are co-corresponding authors of this paper. This study was supported by the National Science Foundation of China, the Shanghai Rising-Star Program, the National Science and Technology Major Project of China.
Link：https://doi.org/10.1016/j.immuni.2022.04.017
