核葡萄球菌有助于微卫星稳定型结直肠癌的抗 PD-1 治疗

IF 48.8 1区 医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2024-09-19 DOI:10.1016/j.ccell.2024.08.019
Xueliang Wang, Yi Fang, Wei Liang, Chi Chun Wong, Huanlong Qin, Yaohui Gao, Meinong Liang, Lei Song, Yongxin Zhang, Miao Fan, Chuanfa Liu, Harry Cheuk-Hay Lau, Lixia Xu, Xiaoxing Li, Wu Song, Junlin Wang, Na Wang, Tao Yang, Mengmiao Mo, Xiang Zhang, Jun Yu
{"title":"核葡萄球菌有助于微卫星稳定型结直肠癌的抗 PD-1 治疗","authors":"Xueliang Wang, Yi Fang, Wei Liang, Chi Chun Wong, Huanlong Qin, Yaohui Gao, Meinong Liang, Lei Song, Yongxin Zhang, Miao Fan, Chuanfa Liu, Harry Cheuk-Hay Lau, Lixia Xu, Xiaoxing Li, Wu Song, Junlin Wang, Na Wang, Tao Yang, Mengmiao Mo, Xiang Zhang, Jun Yu","doi":"10.1016/j.ccell.2024.08.019","DOIUrl":null,"url":null,"abstract":"<p>Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, <em>Fusobacterium nucleatum</em> (<em>Fn</em>), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with <em>Fn</em>-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from <em>Fn</em>-low counterparts. Single <em>Fn</em> administration also potentiates anti-PD-1 efficacy in murine allografts and CD34<sup>+</sup>-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral <em>Fn</em> generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8<sup>+</sup> T cells, inducing <em>Tbx21</em> promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8<sup>+</sup> T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in <em>Fn</em> abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral <em>Fn</em> predicts favorable response to anti-PD-1 therapy, indicating <em>Fn</em> as a potential biomarker of immunotherapy response in MSS CRC.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"196 1","pages":""},"PeriodicalIF":48.8000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer\",\"authors\":\"Xueliang Wang, Yi Fang, Wei Liang, Chi Chun Wong, Huanlong Qin, Yaohui Gao, Meinong Liang, Lei Song, Yongxin Zhang, Miao Fan, Chuanfa Liu, Harry Cheuk-Hay Lau, Lixia Xu, Xiaoxing Li, Wu Song, Junlin Wang, Na Wang, Tao Yang, Mengmiao Mo, Xiang Zhang, Jun Yu\",\"doi\":\"10.1016/j.ccell.2024.08.019\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, <em>Fusobacterium nucleatum</em> (<em>Fn</em>), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with <em>Fn</em>-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from <em>Fn</em>-low counterparts. Single <em>Fn</em> administration also potentiates anti-PD-1 efficacy in murine allografts and CD34<sup>+</sup>-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral <em>Fn</em> generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8<sup>+</sup> T cells, inducing <em>Tbx21</em> promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8<sup>+</sup> T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in <em>Fn</em> abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral <em>Fn</em> predicts favorable response to anti-PD-1 therapy, indicating <em>Fn</em> as a potential biomarker of immunotherapy response in MSS CRC.</p>\",\"PeriodicalId\":9670,\"journal\":{\"name\":\"Cancer Cell\",\"volume\":\"196 1\",\"pages\":\"\"},\"PeriodicalIF\":48.8000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ccell.2024.08.019\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2024.08.019","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

微卫星稳定(MSS)结直肠癌(CRC)通常对抗程序性死亡-1(PD-1)疗法具有抗药性。在这里,我们发现一种 CRC 病原体--核酸镰刀菌(Fn)--能使 MSS CRC 对抗 PD-1 产生敏感性。将 Fn 高的 MSS CRC 患者的粪便微生物群移植(FMT)给携带 MSS CRC 的无菌小鼠,与 Fn 低的患者的粪便微生物群移植相比,可使小鼠对抗 PD-1 敏感。单次给予 Fn 还能增强小鼠异体移植和携带 MSS CRC 的 CD34+ 人源化小鼠的抗 PD-1 疗效。从机理上讲,我们证明瘤内 Fn 会产生大量丁酸,抑制 CD8+ T 细胞中的组蛋白去乙酰化酶(HDAC)3/8,诱导 Tbx21 启动子 H3K27 乙酰化和表达。TBX21 可转录抑制 PD-1,缓解 CD8+ T 细胞衰竭并促进效应器功能。支持这一观点的是,敲除 Fn 中的丁酸产生基因会取消其抗 PD-1 的促进作用。在MSS CRC患者中,瘤内高Fn可预测抗PD-1疗法的良好反应,这表明Fn是MSS CRC免疫疗法反应的潜在生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer

Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn-low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
期刊最新文献
Elucidating acquired PARP inhibitor resistance in advanced prostate cancer Mutation burden and anti-PD-1 outcomes are not universally associated with immune cell infiltration or lymphoid activation Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade Unraveling the tumor-initiating cells in hepatocellular carcinoma
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1