1. Shaping immune landscape of colorectal cancer by cholesterol metabolites
- Author
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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, and Chenqi Xu
- Subjects
Colorectal Cancer with Microsatellite Stability ,Asynchronous Cholesterol Biosynthesis ,Distal Cholesterol Precursors ,Th17 ,Cyp51 Targeted Therapy ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - 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.
- Published
- 2024
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