Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer

Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability-high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential.

We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis.

In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer.

Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.