Nature：使用泛癌图谱研究肿瘤相关巨噬细胞作为免疫疗法反应的调节因子-动脉网

Nature：Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response

Nature 等信源发布 2024-07-06 12:28

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AbstractThe paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity.

摘要由于个体发育和/或局部刺激的差异，巨噬细胞表征的范例已经从简单的M1/M2二分法发展到更复杂的模型，该模型涵盖了广泛的巨噬细胞表型多样性。我们目前缺乏一个深入的肿瘤相关巨噬细胞（TAMs）泛癌单细胞RNA-seq（scRNAseq）图谱，可以充分捕捉这种复杂性。

In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver.

此外，对巨噬细胞多样性的更多了解可能有助于解释癌症患者对免疫疗法的可变反应。我们的图谱包括完善的巨噬细胞亚群以及许多其他亚群。我们将巨噬细胞组成与肿瘤表型联系起来，并显示巨噬细胞亚群在肝脏等部位生长的原发性和转移性肿瘤之间可能有所不同。

We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 + ) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes.

我们还检查了巨噬细胞-T细胞功能性串扰，并确定了与T细胞活化相关的TAM的两个子集。在一大批免疫检查点抑制剂治疗的患者（CPI1000+）中对TAM特征的分析确定了与反应相关的多个TAM亚群，包括存在上调胶原相关基因的TAM亚群。

Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer..

最后，我们展示了我们的数据作为资源和参考图谱的实用性，用于使用投影绘制新型巨噬细胞数据集。总体而言，这些进展代表了巨噬细胞分类和克服癌症免疫疗法耐药性的重要一步。。

IntroductionThe complex interplay between cancer-cell intrinsic factors and the tumour microenvironment (TME) determine the prognosis, progression and efficacy of treatment for cancer. Tumour-associated macrophages (TAMs) are a highly diverse and prominent component of this environment, and much like their functional diversity in the body1, whether as microglia in the brain, Kupffer cells in the liver and Langerhans cells lining the skin epithelium, they also form a diverse array of functions within the heterogeneous architecture of the tumour2.

引言癌细胞内在因素与肿瘤微环境（TME）之间复杂的相互作用决定了癌症治疗的预后，进展和疗效。肿瘤相关巨噬细胞（TAMs）是这种环境中高度多样化和突出的组成部分，就像它们在体内的功能多样性一样，无论是大脑中的小胶质细胞，肝脏中的库普弗细胞还是皮肤上皮衬里的朗格汉斯细胞，它们也在肿瘤的异质结构内形成多种功能2。

Specifically, TAMs have been shown to promote invasion of cancer cells into the surrounding tissues, vascularization of tumours, escape of cancer cells into tumour blood vessels, extravasation of cancer cells from the circulation into metastatic sites like the lungs, and suppression of anti-tumour immunity2,3,4.In most tumour types, the density of TAMs correlates with poor prognosis5,6,7,8, but in some like colorectal cancer the opposite is true9,10,11,12.

具体而言，TAM已被证明可促进癌细胞向周围组织的侵袭，肿瘤的血管形成，癌细胞逃逸到肿瘤血管中，癌细胞从循环外渗到肺部等转移部位，以及抑制抗肿瘤免疫2,3,4。在大多数肿瘤类型中，TAM的密度与预后不良相关5,6,7,8，但在一些类似结直肠癌的情况下，情况恰恰相反9,10,11,12。

Macrophage classification has historically followed a bipartite system named M1/M2, with M1 macrophages associated with inflammatory functionality, and M2 macrophages associated with anti-inflammatory properties. Whilst the paradigm for the role of macrophages in the TME has evolved with research, moving from a simpler M1/M2 dichotomy defined based on the inflammatory axis of TAMs in vitro13, to more complicated models reflecting the full spectrum of their functional diversity14,15, we currently lack a comprehensive atlas of TAM phenotypes that utilizes the full breadth of scRNAseq data available, with existing efforts focusing on broader subsets of immune cells such as all monocytes and their developmental derivatives (including macrophages), or all myeloid cells and lymphoid.

巨噬细胞分类历史上遵循称为M1/M2的二分系统，M1巨噬细胞与炎症功能相关，M2巨噬细胞与抗炎特性相关。虽然巨噬细胞在TME中的作用的范例随着研究而发展，从基于体外TAMs炎症轴定义的更简单的M1/M2二分法13转变为反映其功能多样性全谱的更复杂模型14,15，我们目前缺乏一个综合的TAM表型图谱，该图谱利用了可用的scRNAseq数据的全部范围，现有的努力集中在更广泛的免疫细胞亚群上，如所有单核细胞及其发育衍生物（包括巨噬细胞）或所有髓样细胞和淋巴样细胞。

Data availability

数据可用性

The scRNAseq atlas generated in this study has been deposited in Zenodo as a Seurat object under accession code 11222158. All other data are available in the article and its Supplementary files or from the corresponding author upon request. Source data are provided with this paper.

本研究中生成的scRNAseq图谱已作为Seurat对象存放在Zenodo，登录号为11222158。所有其他数据均可在文章及其补充文件中获得，或应要求从通讯作者处获得。本文提供了源数据。

Code availability

代码可用性

The code associated with this manuscript is available at https://github.com/alexcoulton/macrophage-atlas and under the following Zenodo https://doi.org/10.5281/zenodo.11221774.

与这份手稿相关的代码可以在https://github.com/alexcoulton/macrophage-atlas在下面的Zenodo下https://doi.org/10.5281/zenodo.11221774.

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Arya，S.，Kemp，S.E.，Jefferis，G.＆Mount，D.RANN：使用L2度量的快速最近邻搜索（Wraps ANN库）。（2019年）。Coulton，A。等人，2024年。巨噬细胞图谱，https://doi.org/10.5281/zenodo.11221774（2024年）。下载referencesAcknowledgementsK。Litchfield由英国医学研究委员会（MR/P014712/1和MR/V033077/1），Rosetrees Trust和Cotswold Trust（A2437）以及CRUK（C69256/A30194）资助。

A. Coulton is funded by the Melanoma Research Alliance (award reference 686061). C.E.L acknowledges grant support for her work from Prostate Cancer UK (RIA16-ST2-022). We are thankful to Joe Brock of the Francis Crick Institute, who produced the anatomical illustration used in Fig. 1.Author informationAuthor notesThese authors contributed equally: Claire E.

A、库尔顿由黑色素瘤研究联盟资助（奖项参考号686061）。C、 E.L感谢英国前列腺癌协会（RIA16-ST2-022）对她的工作的资助。我们感谢弗朗西斯·克里克研究所的乔·布鲁克，他制作了图1中使用的解剖学插图。作者信息作者注意到这些作者做出了同样的贡献：克莱尔·E。

Lewis, Kevin Litchfield.Authors and AffiliationsThe Tumour Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, WC1E 6DD, UKAlexander Coulton, Jun Murai, Danwen Qian, Krupa Thakkar & Kevin LitchfieldDepartment of Oncology and Metabolism, University of Sheffield Medical School, Beech Hill Road, Sheffield, Yorkshire, S10 2RX, UKClaire E.

刘易斯，凯文·利奇菲尔德。作者和附属机构伦敦大学学院癌症研究所肿瘤免疫基因组学和免疫监视（TIGI）实验室，WC1E 6DD，英国亚历山大·库尔顿，Jun Murai，Danwen Qian，Krupa Thakkar＆Kevin Litchfield谢菲尔德大学医学院肿瘤学和代谢系，比奇山路，谢菲尔德，约克郡，S10 2RX，UKClaire E。

LewisAuthorsAlexander CoultonView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsA.C. performed data collation, atlas construction, analysis, wrote the manuscript, produced figures. J.M. performed data collation, atlas construction and analysis. D.Q. assisted with the MANA score analysis. K.T. provided the CPI1000+ data. C.E.L.

PubMed谷歌学术贡献。C、进行数据整理，图谱构建，分析，撰写手稿，生成数字。J、 M.进行数据整理，图谱构建和分析。D、 Q.协助进行MANA得分分析。K、 T.提供了CPI1000+数据。C、 E.L。

and K.L. provided supervision and oversight of the project.Corresponding authorsCorrespondence to.

K.L.对该项目进行监督。通讯作者通讯。

Claire E. Lewis or Kevin Litchfield.Ethics declarations

克莱尔·刘易斯或凯文·利奇菲尔德。道德宣言

Competing interests

相互竞争的利益

K.L. has the following disclosures (all unrelated to the current work): patent on indel burden and CPI response pending, patent on ctDNA minimal residual disease calling methods, patent pending on a lung cancer vaccine; speaker fees from Roche tissue diagnostics and Ellipses pharma; research funding from CRUK TDL/Ono/LifeArc alliance and Genesis Therapeutics; and consulting roles with Monopteros Therapeutics, Saga diagnostics, Kynos Therapeutics and Tempus Labs, Inc.

K、 L.有以下披露（均与当前工作无关）：indel负担和CPI反应专利正在申请中，ctDNA最小残留疾病呼叫方法专利正在申请中，肺癌疫苗专利正在申请中；罗氏组织诊断公司和椭圆制药公司的演讲者费用；CRUK TDL/Ono/LifeArc联盟和Genesis Therapeutics的研究资金；并担任Monopteros Therapeutics，Saga diagnostics，Kynos Therapeutics和Tempus Labs，Inc.的咨询角色。

Again unrelated to this work, K.L. is currently employed by Isomorphic Labs. J.M. is an employee of Ono Pharmaceutical. The other authors declare no competing interests..

同样与这项工作无关，K.L.目前受雇于Isomorphic Labs。J、 M.是大野制药的员工。其他作者声明没有利益冲突。。

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Reprints and permissionsAbout this articleCite this articleCoulton, A., Murai, J., Qian, D. et al. Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response.

转载和许可本文引用本文Coulton，A.，Murai，J.，Qian，D。等人使用泛癌图谱研究肿瘤相关巨噬细胞作为免疫治疗反应的调节剂。

Nat Commun 15, 5665 (2024). https://doi.org/10.1038/s41467-024-49885-8Download citationReceived: 27 February 2023Accepted: 24 June 2024Published: 06 July 2024DOI: https://doi.org/10.1038/s41467-024-49885-8Share 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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Cancer genomicsCancer microenvironmentGene regulation in immune cellsMonocytes and macrophagesTumour immunology

免疫细胞中的癌症基因组扫描微环境基因调控单核细胞和巨噬细胞免疫

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