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Single-cell RNA sequencing of immune cells in gastric cancer patients.

ABSTRACT: Cancer immunotherapy has achieved positive clinical responses in the treatment of various cancers, including gastric cancer (GC). In this study, we characterized the heterogeneity of T cells isolated from GC patients at the single-cell level using single-cell RNA sequencing. We identified different immune cell subtypes and their heterogeneous transcription factors and depicted their developmental trajectories. In particular, we focused on exhausted CD8⁺ cells and Tregs and discovered that, as compared to control, the IRF8 transcription factor was downregulated in CD8⁺ tumour-infiltrating lymphocytes (TILs) from GC tissues, and that GC patients with lower IRF8 levels in blood CD8⁺ T cells tended to be a at a more advanced disease stage. These findings provide a theoretical basis for targeted immune therapy in GC.

SUBMITTER: Fu K

PROVIDER: S-EPMC7041746 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Single-cell RNA sequencing of immune cells in gastric cancer patients.

Fu Kai K Hui Bingqing B Wang Qian Q Lu Chen C Shi Weihong W Zhang Zhigang Z Rong Dawei D Zhang Betty B Tian Zhaofeng Z Tang Weiwei W Cao Hongyong H Wang Xuehao X Chen Ziyi Z

Aging 20200210 3

Cancer immunotherapy has achieved positive clinical responses in the treatment of various cancers, including gastric cancer (GC). In this study, we characterized the heterogeneity of T cells isolated from GC patients at the single-cell level using single-cell RNA sequencing. We identified different immune cell subtypes and their heterogeneous transcription factors and depicted their developmental trajectories. In particular, we focused on exhausted CD8<sup>+</sup> cells and Tregs and discovered ...[more]

PMID: 32039830

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Project description:Single-cell RNA sequencing (scRNAseq) technology is still relatively new in the field of gastric cancer immunology but gaining significant traction. This technology now provides unprecedented insights into the intratumoral and intertumoral heterogeneities at the immunological, cellular, and molecular levels. Within the last few years, a volume of publications reported the usefulness of scRNAseq technology in identifying thus far elusive immunological mechanisms that may promote and impede gastric cancer development. These studies analyzed datasets generated from primary human gastric cancer tissues, metastatic ascites fluid from gastric cancer patients, and laboratory-generated data from in vitro and in vivo models of gastric diseases. In this review, we overview the exciting findings from scRNAseq datasets that uncovered the role of critical immune cells, including T cells, B cells, myeloid cells, mast cells, ILC2s, and other inflammatory stromal cells, like fibroblasts and endothelial cells. In addition, we also provide a synopsis of the initial scRNAseq findings on the interesting epithelial cell responses to inflammation. In summary, these new studies have implicated roles for T and B cells and subsets like NKT cells in tumor development and progression. The current studies identified diverse subsets of macrophages and mast cells in the tumor microenvironment, however, additional studies to determine their roles in promoting cancer growth are needed. Some groups specifically focus on the less prevalent ILC2 cell type that may contribute to early cancer development. ScRNAseq analysis also reveals that stromal cells, e.g., fibroblasts and endothelial cells, regulate inflammation and promote metastasis, making them key targets for future investigations. While evaluating the outcomes, we also highlight the gaps in the current findings and provide an assessment of what this technology holds for gastric cancer research in the coming years. With scRNAseq technology expanding rapidly, we stress the need for periodic review of the findings and assess the available scRNAseq analytical tools to guide future work on immunological mechanisms of gastric carcinogenesis. .

Project description:BackgroundThere is still a therapeutic challenge in treating gastric cancer (GC) due to its high incidence and poor prognosis. Collagen type V alpha 2 (COL5A2) is increased in various cancers, yet it remains unclear how it contributes to the prognosis and immunity of GC.MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to download transcriptome profiling (TCGA-STAD; GSE84437), single-cell RNA sequencing (scRNA-seq) data (GSE167297) and clinical information. COL5A2 expression and its relationship with clinicopathological factors were analyzed. We conducted survival analysis and Cox regression analysis to evaluate the prognosis and independent factors of GC. Co-expressed analysis was also performed. To identify the underlying mechanism, we conducted analyses of differentially expressed genes (DEGs) and functional enrichment. The correlations between COL5A2 expression and immune cell infiltration levels and immune infiltrate gene marker sets were further explored. Additionally, we analyzed the association of COL5A2 expression with immunological checkpoint molecules. Furthermore, the relationship between COL5A2 expression and immunotherapy sensitivity was also investigated.ResultsCOL5A2 expression was elevated in GC. More than this, the scRNA-seq analysis revealed that COL5A2 expression had a spatial gradient. The upregulated COL5A2 was associated with worse overall survival. A significant correlation was found between COL5A2 overexpression and age, T classification and clinical stage in GC. COL5A2 was found to be an independent factor for the unfortunate outcome in Cox regression analysis. The co-expressed genes of COL5A2 were associated with tumor stage or poor survival. Enrichment analysis revealed that the DEGs were mainly associated with extracellular matrix (ECM)-related processes, PI3K-AKT signaling pathway, and focal adhesion. GSEA analyses revealed that COL5A2 was associated with tumor progression-related pathways. Meanwhile, COL5A2 expression was correlated with tumor-infiltrating immune cells. Moreover, immunophenoscore (IPS) analysis and PRJEB25780 cohorts showed that patients with low COL5A2 expression were highly sensitive to immunotherapy.ConclusionsCOL5A2 might act as a prognostic biomarker of GC prognosis and immune infiltration and may provide a therapeutic intervention strategy.

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Single-cell RNA sequencing of immune cells in gastric cancer patients.

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Single-cell RNA sequencing of immune cells in gastric cancer patients.

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