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Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer.

ABSTRACT: Profiling heterologous cell types within tumors is essential to decipher tumor microenvironment that shapes tumor progress and determines the outcome of therapeutic response. Here, we comprehensively characterized transcriptomes of 34,037 single cells obtained from 12 treatment-naïve patients with colorectal cancer. Our comprehensive evaluation revealed attenuated B-cell antigen presentation, distinct regulatory T-cell clusters with different origin and novel polyfunctional tumor associated macrophages associated with CRC. Moreover, we identified expanded XCL1⁺ T-cell clusters associated with tumor mutational burden high status. We further explored the underlying molecular mechanisms by profiling epigenetic landscape and inferring transcription factor motifs using single-cell ATAC-seq. Our dataset and analysis approaches herein provide a rich resource for further study of the impact of immune cells and translational research for human colorectal cancer.

SUBMITTER: Mei Y

PROVIDER: S-EPMC8181206 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer.

Mei Yan Y Xiao Weiwei W Hu Hao H Lu Guanming G Chen Lingdan L Sun Zhun Z Lü Mengdie M Ma Wenhui W Jiang Ting T Gao YuanHong Y Li LiRen L Chen Gong G Wang Zifeng Z Li Hanjie H Wu Duojiao D Zhou Pinghong P Leng Qibin Q Jia Guangshuai G

Clinical and translational medicine 20210601 6

Profiling heterologous cell types within tumors is essential to decipher tumor microenvironment that shapes tumor progress and determines the outcome of therapeutic response. Here, we comprehensively characterized transcriptomes of 34,037 single cells obtained from 12 treatment-naïve patients with colorectal cancer. Our comprehensive evaluation revealed attenuated B-cell antigen presentation, distinct regulatory T-cell clusters with different origin and novel polyfunctional tumor associated macr ...[more]

PMID: 34185431

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Project description:BackgroundLiver metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the precise mechanisms remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) was used to analyze the cellular and molecular heterogeneity between CRC primary lesion and corresponding liver metastasis, and to clarify the characteristics of the tumor microenvironment (TME) in synchronous liver metastasis of CRC.MethodsA case of microsatellite stable (MSS) sigmoid carcinoma with synchronous liver metastasis was selected, and tissues from the primary tumor and the liver metastasis were collected for scRNA-seq. The EdgeR package software was used to identify the differentially expressed genes between cells. Gene Set Enrichment Analysis (GSEA) was performed and the clusterProfiler R package was used for Gene Ontology (GO) enrichment analysis. The SCENIC and CellphoneDB packages were used to reconstruct the transcriptional regulatory networks and to analyze the intercellular interaction network, respectively.ResultsCompared to the primary tumor, the proportion of myeloid cells in the metastatic tumor was significantly increased, while B cells and plasma cells were decreased. In the metastatic tumor, the myeloid-derived suppressor cell (MDSC) characteristic gene, mannose receptor C-type 1 (MRC1) and tumor associated macrophage 2 (TAM2)-related gene, were highly expressed. Furthermore, angiogenesis, oxidative phosphorylation, and endothelial mesenchymal transition (EMT) of myeloid cells were also significantly enhanced. There were less myeloid cells in primary tumors, and these were mainly monocytes and TAM1; while the number of TAM2 was significantly upregulated in the metastatic samples. In liver metastasis, the T cell population was exhausted, and this was accompanied by a significant increase in the number of CD4+ T cells and a decrease in the number of CD8+ T cells. Furthermore, some immune checkpoint molecules were highly expressed. Interactions between myeloid cells and other cell populations appeared to be strong.ConclusionsThe TME of CRC liver metastasis is significantly immunosuppressed. Interactions between myeloid cells and other cell populations in the TME contribute to the establishment of a pro-metastatic niche that promotes colonization and growth of CRC cells in the liver. TAMs may be a potential immunotherapeutic target for MSS CRC.

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Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer.

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Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer.

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