ARF6的肿瘤内在内膜运输形成了一个免疫抑制微环境，该微环境驱动黑色素瘤的发生和对检查点阻断治疗的反应-动脉网

Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy

Nature 等信源发布 2024-08-04 23:39

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AbstractTumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development.

摘要肿瘤-宿主免疫相互作用导致肿瘤微环境（TME）的复杂变化，影响进展，转移和对治疗的反应。虽然很明显癌细胞可以改变免疫环境，但我们对这一过程的理解是不完整的。在这里，我们显示由小GTP酶ARF6介导的质膜上的内吞运输使黑素瘤细胞能够施加免疫抑制性TME，从而加速肿瘤的发展。

This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor.

这种依赖ARF6的TME易受免疫检查点阻断疗法（ICB）的影响，但在鼠黑色素瘤中，ARF6的缺失会导致对ICB的抵抗。同样，患者肿瘤中ARF6的下调与ICB后总体生存率较低相关。从机理上讲，这些表型至少部分由ARF6依赖性再循环来解释，该再循环控制干扰素γ受体的质膜密度。

Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy..

总的来说，我们的研究结果揭示了内膜运输在使肿瘤细胞具有塑造其免疫微环境和对免疫疗法作出反应的能力方面的重要性。。

IntroductionImmune escape, a hallmark of cancer1, involves cancer cell sensing and direct disarming of immune attack. Cancer-cell intrinsic mechanisms of immune escape broadly include 1) altering the immune landscape of the tumour microenvironment (TME), 2) direct and indirect inhibition of CD8+ T cell effector function, and 3) altering tumour antigen expression or presentation (reviewed in refs.

。癌细胞免疫逃逸的内在机制广泛包括1）改变肿瘤微环境（TME）的免疫景观，2）直接和间接抑制CD8+T细胞效应功能，以及3）改变肿瘤抗原表达或呈递（参见参考文献）。

2,3). The TME can be composed of diverse cell types that influence disease progression and response to therapy4. Given the performance and potential of immunotherapy, understanding how tumour cells impose changes on the immune system may improve rational clinical use of current immune checkpoint blockade (ICB) therapies and facilitate the development of new, immune-modulating drugs.In melanoma, emerging evidence supports that a complex TME forms surprisingly early in tumour development5.

2,3）。TME可以由影响疾病进展和对治疗反应的不同细胞类型组成4。鉴于免疫疗法的性能和潜力，了解肿瘤细胞如何对免疫系统施加变化可能会改善当前免疫检查点阻断（ICB）疗法的合理临床使用，并促进新的免疫调节药物的开发。在黑色素瘤中，新出现的证据支持复杂的TME在肿瘤发展的早期惊人地形成5。

In a small set of patient samples that ranged from atypical melanocytic proliferations to vertically invasive primary tumours, cytotoxic T lymphocytes (CTLs) were detected with regulatory T cells (Tregs) and myeloid cells in precursor lesions, and the density of these cells increased with progression to melanoma in situ (antecedent to invasion).

在一小组从非典型黑素细胞增殖到垂直侵袭性原发性肿瘤的患者样本中，在前体病变中用调节性T细胞（Tregs）和骨髓细胞检测到细胞毒性T淋巴细胞（CTL），并且这些细胞的密度随着原位黑色素瘤的进展而增加（入侵之前）。

At the invasive stage, cytokine gradients decorated the TME, which had evolved into complex geospatial microenvironments representing multiple mechanisms of immune suppression, including IFNγ-dependent and independent pathways. These findings suggest that newly transformed melanoma cells may have an innate ability to launch immune evasive programmes and create an immunosuppressive TME.Primary cutaneous melanomas are frequently infiltrated by lymphocytes to varying degrees, and dense infiltration is a favourable prognostic histopathologic feature6.

在侵袭阶段，细胞因子梯度装饰了TME，TME已经演变成复杂的地理空间微环境，代表了多种免疫抑制机制，包括IFNγ依赖性和独立途径。这些发现表明，新转化的黑色素瘤细胞可能具有启动免疫逃避程序并产生免疫抑制性TME的先天能力。原发性皮肤黑色素瘤经常被淋巴细胞不同程度地浸润，密集浸润是一种有利的预后组织病理学特征6。

Despi.

绝望。

Arf6 mRNA in situ hybridizationArf6 mRNA was detected in four μm tissue sections using a custom Arf6 probe (Cat# 1205481-C1, Advanced Cell Diagnostics), targeting a sequence located between the loxP sites of the Arf6f/f allele, and the RNAscope 2.5 HD Reagent Kit—RED (Cat# 3222350, Advanced Cell Diagnostics) according to the manufacturer’s instructions.Lysosome enrichmentRNA interference was performed on UACC.62 cells as described above.

Arf6 mRNA原位杂交根据制造商的说明，使用定制的Arf6探针（Cat#1205481-C1，Advanced Cell Diagnostics）在4μm组织切片中检测Arf6 mRNA，该探针靶向位于Arf6f/f等位基因loxP位点之间的序列，RNAscope 2.5 HD试剂盒RED（Cat#3222350，Advanced Cell Diagnostics）。如上所述，对UACC.62细胞进行溶酶体富集RNA干扰。

Lysosome enrichment was performed using a Lysosome Enrichment Kit (ThermoFisher Scientific, Cat# 89839) according to the manufacturer’s instructions. Briefly, cells were disrupted in the supplied lysis buffers using a Dounce homogenizer. Following centrifugation to pellet debris, supernatants were loaded on 15–30% Optiprep (Millipore-Sigma, Cat# D1556) step gradients and centrifuged at 145,000 × g for 2 h.

。简而言之，使用Dounce匀浆器在提供的裂解缓冲液中破坏细胞。离心沉淀碎片后，将上清液加载到15-30%的Optiprep（Millipore Sigma，Cat#D1556）梯度梯度上，并以145000×g离心2小时。

The lysosome-enriched fractions were collected and pelleted prior to lysis and quantitation for use in western blot analysis.In vivo CD8+ T-cell depletionAt 5 weeks post DF1 RCAS-Cre injection, mice were treated with antibodies prior to tumour onset. Anti-CD8 (200 µg/mouse, Bio X Cell, Cat# BE0117) or rat IgG2b isotype control (200 µg/mouse, Bio X Cell, Cat# BE0090) antibodies were injected intraperitoneally twice per week for 8 weeks or until the tumour measured 2 cm in one dimension.

在裂解和定量之前，收集富含溶酶体的级分并沉淀，以用于蛋白质印迹分析。体内CD8+T细胞消耗在DF1 RCAS-Cre注射后5周，在肿瘤发作之前用抗体处理小鼠。将抗CD8（200μg/小鼠，Bio X细胞，Cat#BE0117）或大鼠IgG2b同种型对照（200μg/小鼠，Bio X细胞，Cat#BE0090）抗体每周两次腹膜内注射8周或直到肿瘤在一维测量为2cm。

CD8+ cell depletion was verified by flow cytometry.In vivo anti-PD-1 treatmentAnti-PD-1 treatment was initiated prior to palpable tumour onset, when microscopic disease was expected, in Arf6WT mice at 5 weeks, and in Arf6f/f mice at 7 weeks. Anti-PD-1 (8 mg/kg, Bio X Cell, Cat# BE0146) was administered intraperitoneally twice per week for 5 weeks or <5 weeks if the tumour reached 2 cm in greatest dimension.

通过流式细胞术验证CD8+细胞消耗。体内抗PD-1治疗抗PD-1治疗在可触及的肿瘤发作之前开始，当预期微观疾病时，在5周的Arf6WT小鼠和7周的Arf6f/f小鼠中开始。抗PD-1（8mg/kg，Bio X Cell，Cat#BE0146）每周两次腹膜内给药5周，如果肿瘤最大尺寸达到2cm，则<5周。

A second cohort of Arf6WT and Arf6f/f mice con.

第二组Arf6WT和Arf6f/f小鼠con。

Data availability

数据可用性

The raw and processed single-cell and bulk RNA sequence data from murine tumours generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession code GSE253094. The publicly released data used in this study are available in the GEO database under accession code GSE129392.

本研究中产生的小鼠肿瘤的原始和处理的单细胞和大量RNA序列数据已保存在Gene Expression Omnibus（GEO）数据库中，登录号为GSE253094。本研究中使用的公开发布数据可在GEO数据库中以登录号GSE129392获得。

The Leeds Melanoma Cohort gene expression dataset is available under restricted access at the EGA under accession number EGAD00010001561. Data access can be granted via the EGA with completion of a data access agreement. The TCGA publicly available data used in this study are available in the Genomic Data Commons database under accession code TCGA-SKCM.

利兹黑色素瘤队列基因表达数据集可在EGA的限制访问下获得，登录号为EGAD00010001561。在完成数据访问协议后，可以通过EGA授予数据访问权限。本研究中使用的TCGA公开可用数据可在基因组数据共享数据库中以登录号TCGA-SKCM获得。

Human datasets can be analyzed through Cancer-Immu: https://bioinfo.vanderbilt.edu/database/Cancer-Immu/. The remaining data are available within the Article, Supplementary Information or Source Data file. Source data are provided with this paper..

人类数据集可以通过Cancer Immu进行分析：https://bioinfo.vanderbilt.edu/database/Cancer-Immu/.其余数据可在文章，补充信息或源数据文件中找到。本文提供了源数据。。

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M., Crowson, Cynthia S., Atkinson, Elizabeth J. A Package for Survival Analysis in R. R package version 3.5-5. The Comprehensive R Archive Network (2023).Download referencesAcknowledgementsWe thank Diana Lim and Nikita Abraham for preparation of scientific graphics and illustrations; J.P. Snook for technical support; the Cell Response and Regulation (CRR) Program from the Huntsman Cancer Institute (HCI); HCI Shared Resources: Research Histology, Research Immunohistochemistry, High Throughput Genomics and Cancer Bioinformatics, Cancer Biostatistics and Preclinical Research Resource; University of Utah Flow Cytometry Core and the Genomics Core; MD Anderson Cancer Center Functional Proteomics Core; the Leeds Institute of Cancer and Pathology, University of Leeds, U.K.; Qi Liu, Hua-Chang Chen and Jing Yang (Vanderbilt University Medical Center) for Cancer-Immu technical support; the Health Data Analytics and Statistics Center, Office of Data Science, Taipei Medical University for statistical support.

M、，Crowson，Cynthia S.，Atkinson，Elizabeth J.R.R软件包版本3.5-5中的生存分析软件包。。下载参考文献致谢我们感谢Diana Lim和Nikita Abraham准备科学图形和插图；J、 P.Snook寻求技术支持；亨斯迈癌症研究所（HCI）的细胞反应与调节（CRR）计划；HCI共享资源：研究组织学，研究免疫组织化学，高通量基因组学和癌症生物信息学，癌症生物统计学和临床前研究资源；犹他大学流式细胞仪核心和基因组学核心；MD安德森癌症中心功能蛋白质组学核心；英国利兹大学利兹癌症与病理学研究所。；刘琦，陈华昌和杨靖（范德比尔特大学医学中心）提供癌症免疫技术支持；台北医科大学数据科学办公室健康数据分析与统计中心提供统计支持。

This project was supported by funding from NIH/NCI P30CA042014 (HCI). A.H.G. has been supported by the American Cancer Society 133649-RSG-19-019-01-CSM and NIH/NCI K08CA188563 and is currently supported by the Department of Pathology at the University of Utah, NIH/NCI R37CA230630 and U.S. Department of Defense (DoD) W81XWH2210910.

该项目得到了NIH/NCI P30CA042014（HCI）的资助。A、 H.G.得到了美国癌症协会133649-RSG-19-019-01-CSM和NIH/NCI K08CA188563的支持，目前得到了犹他大学病理学系，NIH/NCI R37CA230630和美国国防部（DoD）W81XWH2210910的支持。

S.L.H. is supported by NIH/NCI R01CA121118. M.A.W. is supported by .

S、 L.H.由NIH/NCI R01CA121118支持。M、 A.W.由支持。

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PubMed Google ScholarContributionsConceptualization, A.H.G, Y.W.; investigation, Y.W., J.W., E.C.W, C.P.R., A.R., E.D., J.K.H.T., R.K.W., A.H.G.; formal analysis, C.S., K.B. J.M.O, K.C.F., H.A.E.; methodology, S.L.H., K.C.F, M.A.W., A.H.G.; resources, Z.T., M.A.W., S.L.H., Y.N.V.G., M.A.D.; supervision, A.H.G., R.K.W., K.C.F., M.A.W., S.L.H.; writing-original draft, A.H.G, Y.W.; writing-reviewing & editing, A.H.G, Y.W., J.W., E.C.W., J.K.H.T., R.K.W.; funding acquisition, A.H.G.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献概念化，A.H.G，Y.W。；调查，Y.W.，J.W.，E.C.W.，C.P.R.，A.R.，E.D.，J.K.H.T.，R.K.W.，A.H.G。；形式分析，C.S.，K.B.J.M.O，K.C.F.，H.A.E。；方法论，S.L.H.，K.C.F，M.A.W.，A.H.G。；资源，Z.T.，M.A.W.，S.L.H.，Y.N.V.G.，M.A.D。；监督，A.H.G.，R.K.W.，K.C.F.，M.A.W.，S.L.H。；撰写原稿，A.H.G，Y.W。；写作评论与编辑，A.H.G，Y.W.，J.W.，E.C.W.，J.K.H.T.，R.K.W。；资金收购，A.H.G.通讯作者回复。

Allie H. Grossmann.Ethics declarations

艾莉·H·格罗斯曼。道德宣言

Competing interests

相互竞争的利益

M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, Merck, and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, Pfizer, ABM Therapeutics, and LEAD Pharma.

M、 A.D.曾担任罗氏/基因泰克、Array、辉瑞、诺华、BMS、葛兰素史克、赛诺菲-安万特、Vaccinex、Apexigen、卫材、Iovance、默克和ABM Therapeutics的顾问，并担任罗氏/基因泰克、葛兰素史克、赛诺菲-安万特、默克、Myriad、Oncothyreon、辉瑞、ABM Therapeutics和LEAD Pharma向MD Anderson提供研究资助的PI。

The remaining authors declare no competing interests..

其余作者声明没有利益冲突。。

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Nature Communications thanks Hisataka Sabe 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Hisataka Sabe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 articleWee, Y., Wang, J., Wilson, E.C. et al. Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy.

转载和许可本文引用本文Wee，Y.，Wang，J.，Wilson，E.C.等人。ARF6的肿瘤内在内膜运输形成了一种免疫抑制微环境，驱动黑色素瘤的发生和对检查点阻断疗法的反应。

Nat Commun 15, 6613 (2024). https://doi.org/10.1038/s41467-024-50881-1Download citationReceived: 04 January 2024Accepted: 24 July 2024Published: 04 August 2024DOI: https://doi.org/10.1038/s41467-024-50881-1Share 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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