Immune microenvironment characteristics and their implications for immune checkpoint inhibitor efficacy in HER2-overexpressing gastric cancer

Abstract

Abstract HER2-positive gastric cancer is a distinct tumor subtype, accounting for ~10% of gastric cancer cases. It is characterized by HER2 overexpression and responds well to HER2-targeting therapies. Recently, the addition of immune checkpoint inhibitors to HER2-targeting therapies produced satisfactory outcomes in these patients. In the present study, we used gene expression profiles and patient surgical sections to analyze the tumor immune microenvironment characteristics of gastric tumors with high HER2 expression. Several differentially enriched pathways were identified between the HER2 high-expression group and the low-expression group, such as pathways related to cytokine–cytokine receptor interactions, calcium signaling, and cell adhesion molecules. Tumors with high HER2 expression comprised fewer stromal cells and fewer immune cells, and had higher tumor purity. They also presented with lower expression of PD-1, PD-L1, CTLA-4, TIGIT, and LAG-3. In conclusion, our study provides a comprehensive blueprint of the immune microenvironment of HER2-positive gastric tumors. This analysis highlights the importance of considering the tumor microenvironment when assessing response to immune checkpoint inhibitors.