Identifying a CD8T cell signature in the tumor microenvironment to forecast gastric cancer outcomes from sequencing data

Background: The tumor microenvironment (TME) could be critical in carcinogenesis, immune evasion, and treatment response. TME-related genes are limited in their ability to predict gastric cancer (GC) outcomes. We utilized data from The Cancer Genome Atlas (TCGA) to investigate the functional roles of TME-related genes in GC.

Methods: We acquired single-cell data, bulk sequencing data, and clinical characteristics of GC patients from the TCGA database. The CD8T cell genes associated with the TME were selected for bioinformatic analysis in GC. Tumor classification of GC was established through consistent cluster analysis. We then evaluated the prognosis and immune cell infiltration in connection with a CD8T cell-related model for GC.

Results: The single-cell messenger RNA (mRNA) sequencing (scRNA-Seq) dataset of GSE134520 was utilized to investigate the pathogenesis and disease-specific cell types in GC. Interestingly, compared to healthy tissue, the proportions of CD8Tex cells, malignant cells, and gland mucous increased in GC, whereas the proportion of pit mucous decreased in GC. Since CD8Tex cells may play a vital role in pancreatic adenocarcinoma (PAAD), based on the 612 differentially expressed genes (DEGs) involved in CD8Tex cells, TCGA-GC patients were stratified into low- and high-risk groups. The downregulated DEGs in the low-risk G1 group were associated with proteoglycans in cancer, the cGMP-PKG signaling pathway, focal adhesion, and cell adhesion molecules (CAMs), whereas the upregulated DEGs were associated with viral protein interaction with cytokine and cytokine receptors, the tumor necrosis factor (TNF) signaling pathway, the interleukin (IL)-17 signaling pathway, and the chemokine signaling pathway. Combined with univariate Cox analysis, we ultimately identified 23 CD8T cell-related prognostic genes: TCIM, AADAC, SLC2A3, ZNF331, TSC22D3, CMTM3, ZFP36, VIM, CLDND1, GABARAPL1, SOCS3, RGS1, TCEAL9, RGS2, CD59, SPRY1, EMP3, ZEB2, PDE4B, GLIPR1, ERRFI1, and LBH. Using the Cox regression model to prioritize the 23 CD8T cell-related genes, we finally selected 7 genes: CXCR4, AADAC, SLC2A3, CMTM3, RGS2, CD59, and ZEB2.

Conclusions: CD8T cell-related genes have a strong association with tumor classification and immune response in GC patients. A CD8T cell-related signature demonstrated robust prognostic predictive performance for GC. Our findings may reveal novel insights into the diagnosis and treatment of GC.