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空间转录组学揭示了代谢特征通过 iCAF 转化定义口腔鳞状细胞癌肿瘤免疫抑制微环境。

Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma.

机构信息

Department of Oral and Maxillofacial - Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.

Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

Int J Oral Sci. 2024 Jan 30;16(1):9. doi: 10.1038/s41368-023-00267-8.

DOI:10.1038/s41368-023-00267-8
PMID:38287007
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10824761/
Abstract

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.

摘要

肿瘤的进展与肿瘤组织的代谢和微环境的重塑密切相关。口腔鳞状细胞癌（OSCC）是一种代表缺氧肿瘤，具有异质性的内部代谢环境。为了阐明 OSCC 不同代谢区域与肿瘤免疫微环境（TME）之间的关系，对 OSCC 组织进行了单细胞（SC）和空间转录组学（ST）测序。通过使用 SC 和 GSE103322 数据对 SPOTlight 进行去卷积，从 ST 数据中获得 TME 的比例。使用 scMetabolism 计算每个点的代谢活性，并使用 k-means 聚类将所有点分类为高代谢、正常代谢或低代谢区域。与其他区域相比，高代谢区域的 CD4T 细胞浸润和 TGF-β 表达更高。通过 CellPhoneDB 和 NicheNet 细胞间通讯分析发现，在高代谢区域，成纤维细胞可以利用上皮细胞糖酵解产生的乳酸转化为炎症性癌相关成纤维细胞（iCAFs），并且 iCAFs 中 HIF1A 的增加表达促进 CXCL12 的转录表达。CXCL12 的分泌招募调节性 T 细胞（Tregs），导致微环境中 Treg 的浸润和 TGF-β的分泌增加，并促进肿瘤免疫抑制微环境的形成。本研究使用 SC、ST 和 TCGA 批量数据描绘了 OSCC 中上皮细胞-iCAFs-Tregs 的协调工作轴，并强调了治疗的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/5d58ca89ebc5/41368_2023_267_Fig11_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/5496e6c70926/41368_2023_267_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/35411efb2b6e/41368_2023_267_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/2a7324195c3e/41368_2023_267_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/0f8f50dc3d6f/41368_2023_267_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/dcd4b026e89e/41368_2023_267_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/31e84031db1b/41368_2023_267_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bded/10824761/5d58ca89ebc5/41368_2023_267_Fig11_HTML.jpg

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[5]
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[6]
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Front Oncol. 2025-6-19

[7]
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MedComm (2020). 2025-7-1

[8]
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BMC Cancer. 2025-7-1

[9]
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[10]
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本文引用的文献

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