Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Abstract

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.

Exploring the current landscape of single‐cell RNA sequencing applications in gastric cancer research

“…A low sequencing depth in scRNA‐seq presents challenges in detecting lowly expressed genes and alternative splicing events 31 . Furthermore, certain cell types, such as granulocytes, prove challenging to target due to their low RNA content and high levels of ribonuclease (RNase) 41 . Collectively, these challenges contribute to the complexities and limitations associated with scRNA‐seq analysis in gastric tumours.…”

Linking dysbiosis to precancerous stomach through inflammation: Deeper than and beyond imaging

“…Emerging technologies such as single-cell RNA-sequencing (scRNA-seq) are delivering unprecedent insights of elusive immune-mediated mechanisms of gastric carcinogenesis by providing a comprehensive view of the cellular landscape and interactions within a tissue at a single-cell resolution, with the potential to contribute towards the development of more effective diagnostics and therapeutic targets (102)(103)(104).…”

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

“…Subsequent studies also showed that TEC participated in the formation of tumor immune tolerance under hypoxia ( 66 ). TEC can interact with CAF through VEGFA in GC ( 67 ).In other tumors, TEC can up regulate the immune checkpoint molecules of T cells and inhibit the activation of T cells ( 68 ). TEC expressing FasL can reduce the number of CD8 + T cells and increase the number of Treg ( 69 ).…”