Shaping immune landscape of colorectal cancer by cholesterol metabolites
Shaping immune landscape of colorectal cancer by cholesterol metabolites
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胆固醇代谢产物对结直肠癌免疫景观的塑造
DOI：
10.1038/s44321-023-00015-9
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发表时间：
2024-01
影响因子：
11.1
通讯作者：
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;B. Song;Zhuozhong Wang;Kang Li;Xin Liu;Guangchuan Wang;Weiwei Yang;Jianfeng Chen;Pei Hao;Zemin Zhang;Zhigang Wang;Zheng-Jiang Zhu;Chenqi Xu
中科院分区：
文献类型：
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作者：
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;B. Song;Zhuozhong Wang;Kang Li;Xin Liu;Guangchuan Wang;Weiwei Yang;Jianfeng Chen;Pei Hao;Zemin Zhang;Zhigang Wang;Zheng-Jiang Zhu;Chenqi Xu
癌症免疫疗法在临床中取得了前所未有的成功，但在一些主要类型的癌症中仍然基本上无效，例如具有微卫星稳定性的结直肠癌（MSS CRC）。因此，研究耐药肿瘤的肿瘤微环境对制定新的干预策略具有重要意义。在这项研究中，我们确定了一个代谢线索，决定了MSS CRC独特的免疫景观。通过分泌远端胆固醇前体，直接激活RORγt， MSS CRC细胞可以使T细胞向结直肠癌中具有明显促肿瘤功能的Th17细胞极化。对大型人类癌症队列的分析揭示了MSS CRC中胆固醇生物合成的非同步模式，这是远端胆固醇前体异常积累的原因。在临床前MSS CRC模型中，通过药理或遗传干预抑制胆固醇生物合成酶Cyp51，降低肿瘤内远端胆固醇前体水平，并通过th17调节机制抑制肿瘤进展。因此，我们的研究揭示了一种新的癌症免疫相互作用机制和一种治疗难治性MSS结直肠癌的干预策略。
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.