DUSP18抑制大肠癌中胆固醇生物合成并促进抗肿瘤免疫-动脉网

Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer

Nature 等信源发布 2024-07-12 10:45

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AbstractTumor cells reprogram their metabolism to produce specialized metabolites that both fuel their own growth and license tumor immune evasion. However, the relationships between these functions remain poorly understood. Here, we report CRISPR screens in a mouse model of colo-rectal cancer (CRC) that implicates the dual specificity phosphatase 18 (DUSP18) in the establishment of tumor-directed immune evasion.

摘要肿瘤细胞重新编程其代谢以产生专门的代谢物，这些代谢物既能促进自身生长，又能使肿瘤免疫逃避。然而，这些功能之间的关系仍然知之甚少。在这里，我们报告了结直肠癌（CRC）小鼠模型中的CRISPR筛选，该模型暗示了双特异性磷酸酶18（DUSP18）在建立肿瘤定向免疫逃避中的作用。

Dusp18 inhibition reduces CRC growth rates, which correlate with high levels of CD8+ T cell activation. Mechanistically, DUSP18 dephosphorylates and stabilizes the USF1 bHLH-ZIP transcription factor. In turn, USF1 induces the SREBF2 gene, which allows cells to accumulate the cholesterol biosynthesis intermediate lanosterol and release it into the tumor microenvironment (TME).

Dusp18抑制降低CRC生长速率，这与高水平的CD8+T细胞活化相关。从机制上讲，DUSP18使USF1 bHLH-ZIP转录因子去磷酸化并稳定。反过来，USF1诱导SREBF2基因，该基因允许细胞积累胆固醇生物合成中间体羊毛甾醇并将其释放到肿瘤微环境（TME）中。

There, lanosterol uptake by CD8+ T cells suppresses the mevalonate pathway and reduces KRAS protein prenylation and function, which in turn inhibits their activation and establishes a molecular basis for tumor cell immune escape. Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity.

在那里，CD8+T细胞对羊毛甾醇的摄取抑制了甲羟戊酸途径，并降低了KRAS蛋白的异戊二烯化和功能，从而抑制了它们的活化，并为肿瘤细胞免疫逃逸奠定了分子基础。。

Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC..

总的来说，我们的研究结果支持这样的观点，即免疫检查点和代谢阻断的结合代表了一种合理设计的，基于机械的和潜在的CRC治疗方法。。

IntroductionWorld-wide, colorectal cancer (CRC) is the third most prevalent and the second most lethal malignancy1,2,3, the current treatment of which consists of surgical resection and chemotherapy4. With the initial success of melanoma and lung cancer treatment, immunotherapy has rapidly become a major treatment option for many solid cancers, including certain molecular subtypes of CRC5,6.

引言在世界范围内，结直肠癌（CRC）是第三大最常见和第二大致命的恶性肿瘤1,2,3，目前的治疗方法包括手术切除和化疗4。随着黑色素瘤和肺癌治疗的初步成功，免疫疗法已迅速成为许多实体癌的主要治疗选择，包括CRC5,6的某些分子亚型。

However, only about 15% of CRC patients currently benefit from immune checkpoint blockade (ICB) therapy6. One reason for this low response rate is that tumors remodel their microenvironment in ways that promote the exhaustion and inactivation of infiltrating CD8+ T cells, thereby leading to “immune escape”.

然而，目前只有约15%的CRC患者受益于免疫检查点阻断（ICB）治疗6。这种低反应率的一个原因是肿瘤以促进浸润性CD8+T细胞耗竭和失活的方式重塑其微环境，从而导致“免疫逃逸”。

CD8+ T cells initially infiltrate tumors and specifically recognize tumor antigens in order to initiate killing5. However, tumor cells can counter this by contributing to the formation of a variety of immunosuppressive tumor microenvironments (TMEs)7,8. These can limit the infiltration, activation and cytotoxicity of CD8+ T cells by reducing the display of MHC-I molecules on tumor cells9, suppressing IFN signaling10, repressing chemokine production11, altering the composition of the extracellular matrix12, and increasing the expression of co-inhibitory molecules such as PD-L113,14.

CD8+T细胞最初浸润肿瘤并特异性识别肿瘤抗原以启动杀伤5。然而，肿瘤细胞可以通过促进各种免疫抑制性肿瘤微环境（TME）的形成来对抗这种情况7,8。这些可以通过减少MHC-I分子在肿瘤细胞上的显示9，抑制IFN信号传导10，抑制趋化因子产生11，改变细胞外基质12的组成以及增加共抑制分子如PD-L113,14的表达来限制CD8+T细胞的浸润，活化和细胞毒性。

For example, TRIB3 can reduce CD8+ T cell infiltration and induce immune evasion by inhibiting the STAT1-CXCL10 axis in CRC15. Loss of mitochondrial electron transport chain complex II has also been shown to increase antigen presentation and T cell-mediated killing16. Oncogenic KRAS in tumor cells can inhibit the expression of IRF2, leading to high expression of CXCL3, which promotes the migration of myeloid-derived stem cells into the TME17.

例如，TRIB3可以通过抑制CRC15中的STAT1-CXCL10轴来减少CD8+T细胞浸润并诱导免疫逃避。线粒体电子传递链复合物II的丢失也被证明会增加抗原呈递和T细胞介导的杀伤16。肿瘤细胞中的致癌KRAS可以抑制IRF2的表达，导致CXCL3的高表达，从而促进骨髓来源的干细胞向TME17的迁移。

Finally, the down-regulation of tumor ACSL4 can inhibit ferr.

最后，肿瘤ACSL4的下调可以抑制ferr。

Data availability

数据可用性

The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under the accession number GSE264145. The mass spectrometry proteomics data of MC38 cells generated in this study have been deposited to the ProteomeXchange Consortium database (http://proteomecentral.proteomexchange.

本研究中产生的RNA-seq数据已保存在Gene Expression Omnibus（GEO）数据库中，登录号为GSE264145。这项研究中产生的MC38细胞的质谱蛋白质组学数据已保存到ProteomeXchange Consortium数据库中(http://proteomecentral.proteomexchange.

org) under accession code PXD053284. The CRISPR screens data are provided in Supplementary Data 1. The cholesterol metabolomics data are provided in Supplementary Data 5. The transcriptomic data and methylation data used in this study are available in the CRC cases in The Cancer Genome Atlas (TCGA) database (https://portal.gdc.cancer.gov/).

org），登录号为PXD053284。CRISPR屏幕数据在补充数据1中提供。胆固醇代谢组学数据在补充数据5中提供。本研究中使用的转录组数据和甲基化数据可在癌症基因组图谱（TCGA）数据库的CRC病例中获得(https://portal.gdc.cancer.gov/)。

A public single-cell RNA-seq data were available in the GEO database under the accession number GSE178341. The transcription factor binding site prediction was performed online with the JASPAR database (https://jaspar.genereg.net/) and humanTFDB database (http://bioinfo.life.hust.edu.cn/HumanTFDB). A public USF1 ChIP-seq data were available in the GEO database under accession number GSE32465.

GEO数据库中提供了公共单细胞RNA-seq数据，登录号为GSE178341。转录因子结合位点预测是通过JASPAR数据库在线进行的(https://jaspar.genereg.net/)和humanTFDB数据库(http://bioinfo.life.hust.edu.cn/HumanTFDB)。GEO数据库中提供了公开的USF1 ChIP-seq数据，登录号为GSE32465。

The remaining data are available within the Article, Supplementary Information or Source data file. Source data are provided with this paper..

其余数据可在文章，补充信息或源数据文件中找到。。。

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Download referencesAcknowledgementsThe authors thank Profs. Jinfang Zhang (Wuhan University, Wuhan, China) for B16-F10 cells and Congqing Jiang (Wuhan University, Wuhan, China) for CRC patient samples. This work was supported by grants from the National Nature Science Foundation of China (32270828, 92057108, 81772609 to Y.L.); the Special Foundation for Major Science and Technology Program of Hubei Province (2022ACA005 to Y.L.); the Fundamental Research Funds for the Central Universities (2042022dx0003, 2042021kf0229 to Y.L.); Sino-foreign Joint Scientific Research Platform Seed Fund of Wuhan University (WHUZZJJ202204 to Y.L.); Technical support from Instrument Platform Center (Medical Research Institute, Wuhan University, Wuhan, China) and support from Mass Spectrometry Platform (College of Life Science, Wuhan University, Wuhan, China).Author informationAuthors and AffiliationsDepartment of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, ChinaXiaojun Zhou, Genxin Wang, Chenhui Tian, Lin Du & Youjun LiFrontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, 430071, ChinaXiaojun Zhou, Genxin Wang, Chenhui Tian, Lin Du & Youjun LiDivision of Hematology/Oncology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USAEdward V.

下载参考文献致谢作者感谢Profs。张金芳（武汉大学，武汉，中国）用于B16-F10细胞，姜从清（武汉大学，武汉，中国）用于CRC患者样品。这项工作得到了国家自然科学基金（322708289205710881772609给Y.L.）的资助；湖北省重大科技专项基金（2022ACA005至Y.L.）；中央大学基础研究基金（2042022DX00032041KF0229至Y.L.）；；仪器平台中心（武汉大学医学研究所，中国武汉）的技术支持和质谱平台（武汉大学生命科学学院，中国武汉）的支持。作者信息作者和附属机构武汉大学中南医院结直肠和肛门外科，武汉大学生命科学学院湖北省细胞稳态重点实验室，湖北武汉，430072，周晓军，王根新，田晨辉，杜林和于军武汉大学泰康生命医学中心医学研究所免疫与代谢科学中心，湖北武汉，430071，周晓军，王根新，田晨辉，杜林和于军，美国宾夕法尼亚州匹兹堡市匹兹堡市匹兹堡儿童医院血液学/肿瘤学系，15224，美国爱德华五世。

ProchownikDepartment of Microbiology and Molecular Genetics of UPMC, Pittsburgh, PA, 15224, USAEdward V. ProchownikThe Pittsburgh Liver Research Center, The Hillman Cancer Institute of UPMC, Pittsburgh, PA, 15224, USAEdward V. ProchownikAuthorsXiaojun ZhouView author publicationsYou can also s.

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PubMed Google ScholarContributionsX.Z. and Y.L. designed the study; X.Z. performed most of the experiments; X.Z., G.W., C.T., and L.D. constructed plasmids; X.Z. performed to analyze sequencing and clinical data; X.Z., G.W. performed animal experiments. All authors discussed the results.

PubMed谷歌学术贡献x。Z、和Y.L.设计了这项研究；十、 Z.进行了大部分实验；十、 Z.，G.W.，C.T。和L.D.构建的质粒；十、 Z.进行测序和临床数据分析；十、 Z.，G.W.进行了动物实验。。

X.Z., E.P., and Y.L. wrote the manuscript with comments from all authors.Corresponding authorCorrespondence to.

十、 Z.，E.P。和Y.L.撰写了手稿，并附上了所有作者的评论。。

Youjun Li.Ethics declarations

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Nature Communications thanks Ping-Chih Ho, Weiyi Peng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢Ping Chih Ho，Weiyi Peng和另一位匿名审稿人对这项工作的同行评审做出的贡献。可以获得同行评审文件。

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Reprints and permissionsAbout this articleCite this articleZhou, X., Wang, G., Tian, C. et al. Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer.

转载和许可本文引用本文Zhou，X.，Wang，G.，Tian，C。等人。抑制DUSP18会损害胆固醇的生物合成并促进结直肠癌的抗肿瘤免疫力。

Nat Commun 15, 5851 (2024). https://doi.org/10.1038/s41467-024-50138-xDownload citationReceived: 05 February 2024Accepted: 02 July 2024Published: 12 July 2024DOI: https://doi.org/10.1038/s41467-024-50138-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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