CD8 + T-Cell-Related Genes: Deciphering Their Role in the Pancreatic Adenocarcinoma TME and Their Effect on Prognosis.

Background: Because of the unique tumor microenvironment (TME), immunotherapy and targeted therapies have shown limited efficacy in treating pancreatic adenocarcinoma (PAAD). CD8 + T cells play crucial roles in regulating the TME in PAAD; therefore, exploring the function of CD8 + T-cell-related genes (CD8RGs) in PAAD has high potential clinical value and could provide a comprehensive understanding of the microenvironment of PAAD.

Methods: We employed the weighted gene coexpression network analysis and CIBERSORT algorithms to assess PAAD transcriptome data from The Cancer Genome Atlas (TCGA) dataset and identify modules strongly associated with CD8 + T cell infiltration. Using least absolute shrinkage and selection operator regression analysis and Kaplan-Meier curves, we developed a prognostic risk score model for patients with PAAD. We validated this model using single-cell and transcriptome datasets obtained from the Gene Expression Omnibus (GEO). We also examined the correlations between the risk score and factors such as the TME, clinical characteristics, and tumor mutation burden (TMB). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed on differentially expressed genes between the high- and low-risk groups. In addition, the Tumor Immune Dysfunction and Exclusion website and "pRRophetic" R package were used to predict response to immunotherapy and chemotherapy in the high- and low-risk groups, respectively. Finally, we analyzed the expressions of hub genes at the cellular level with quantitative real-time PCR.

Results: A risk model based on five CD8RGs was established and validated using TCGA and GEO datasets. The low-risk group exhibited significantly longer overall and progression-free survival. A positive correlation between the TMB and the risk score was observed. The TME analysis revealed a significant correlation between the risk score and immune function, as well as immune checkpoints. The expression of hub genes was significantly correlated with the infiltration level of CD8 + T cells. The high-risk group responded better to immunotherapy, paclitaxel, cisplatin, mitomycin C, afatinib (BIBW2992), and gefitinib. In contrast, the low-risk group showed higher sensitivity to sunitinib, MK.2206, palbociclib (PD.0332991), and axitinib. Compared with that in normal pancreatic epithelial cells, the expression levels of BCL11A, PHOSPHO1, and GNG7 were significantly decreased, while those of KLK11 and VCAM1 were significantly increased in pancreatic tumor cells.

Conclusions: CD8RGs play an important role in regulating the TME of PAAD. Five hub genes-BCL11A, KLK11, GNG7, PHOSPHO1, and VCAM1-are closely associated with the prognosis of PAAD patients, providing new references for the exploration of biomarkers. Furthermore, our findings offer novel insights for clinical decision-making.