scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory.

The tumor microenvironment (TME) in gastric cancer (GC) has been shown to be important for tumor control but the specific characteristics for GC are not fully appreciated. We generated an atlas of 166,533 cells from 10 GC patients with matched paratumor tissues and blood. Our results show tumor-associated stromal cells (TASCs) have upregulated activity of Wnt signaling and angiogenesis, and are negatively correlated with survival. Tumor-associated macrophages and LAMP3 DCs are involved in mediating T cell activity and form intercellular interaction hubs with TASCs. Clonotype and trajectory analysis demonstrates that Tc17 (IL-17CD8 T cells) originate from tissue-resident memory T cells and can subsequently differentiate into exhausted T cells, suggesting an alternative pathway for T cell exhaustion. Our results indicate that IL17 cells may promote tumor progression through IL17, IL22, and IL26 signaling, highlighting the possibility of targeting IL17 cells and associated signaling pathways as a therapeutic strategy to treat GC.