EMBO Molecular Medicine (Jan 2024)
Shaping immune landscape of colorectal cancer by cholesterol metabolites
- Yibing Bai,
- Tongzhou Li,
- Qinshu Wang,
- Weiqiang You,
- Haochen Yang,
- Xintian Xu,
- Ziyi Li,
- Yu Zhang,
- Chengsong Yan,
- Lei Yang,
- Jiaqian Qiu,
- Yuanhua Liu,
- Shiyang Chen,
- Dongfang Wang,
- Binlu Huang,
- Kexin Liu,
- Bao- Liang Song,
- Zhuozhong Wang,
- Kang Li,
- Xin Liu,
- Guangchuan Wang,
- Weiwei Yang,
- Jianfeng Chen,
- Pei Hao,
- Zemin Zhang,
- Zhigang Wang,
- Zheng-Jiang Zhu,
- Chenqi Xu
Affiliations
- Yibing Bai
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Tongzhou Li
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences
- Qinshu Wang
- School of Life Science and Technology, ShanghaiTech University
- Weiqiang You
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
- Haochen Yang
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Xintian Xu
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Ziyi Li
- Beijing Advanced Innovation Center for Genomics, BIOPIC and School of Life Sciences, Peking University
- Yu Zhang
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Chengsong Yan
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Lei Yang
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Jiaqian Qiu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences
- Yuanhua Liu
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Shiyang Chen
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Dongfang Wang
- Beijing Advanced Innovation Center for Genomics, BIOPIC and School of Life Sciences, Peking University
- Binlu Huang
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Kexin Liu
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Bao- Liang Song
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University
- Zhuozhong Wang
- The Second Affiliated Hospital of Harbin Medical University
- Kang Li
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University
- Xin Liu
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Guangchuan Wang
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Weiwei Yang
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Jianfeng Chen
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Pei Hao
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Zemin Zhang
- Beijing Advanced Innovation Center for Genomics, BIOPIC and School of Life Sciences, Peking University
- Zhigang Wang
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
- Zheng-Jiang Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences
- Chenqi Xu
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- DOI
- https://doi.org/10.1038/s44321-023-00015-9
- Journal volume & issue
-
Vol. 16,
no. 2
pp. 334 – 360
Abstract
Abstract Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer–immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.
Keywords
- Colorectal Cancer with Microsatellite Stability
- Asynchronous Cholesterol Biosynthesis
- Distal Cholesterol Precursors
- Th17
- Cyp51 Targeted Therapy
