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

Zheqi Liu1,2, Zhen Zhang1, Yu Zhang1, Wenkai Zhou1, Xu Zhang1, Canbang Peng3, Tong Ji2, Xin Zou4,5, Zhiyuan Zhang1,6, Zhenhu Ren1,6

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International Journal of Oral Science ›› 2024, Vol. 16 ›› Issue (0) : 9. DOI: 10.1038/s41368-023-00267-8

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

  • Zheqi Liu1,2, Zhen Zhang1, Yu Zhang1, Wenkai Zhou1, Xu Zhang1, Canbang Peng3, Tong Ji2, Xin Zou4,5, Zhiyuan Zhang1,6, Zhenhu Ren1,6
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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.

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Zheqi Liu, Zhen Zhang, Yu Zhang, Wenkai Zhou, Xu Zhang, Canbang Peng, Tong Ji, Xin Zou, Zhiyuan Zhang, …Zhenhu Ren. Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma. International Journal of Oral Science, 2024, 16(0): 9 https://doi.org/10.1038/s41368-023-00267-8

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