Comprehensive exploration of immune checkpoint-related genes in the prognosis and tumor immune microenvironment of pancreatic adenocarcinoma

•Pancreatic Adenocarcinoma (PAAD) exhibits a universally poor prognosis.•Tumor Immune Microenvironment (TIME) affected the development of tumor.•Immune Checkpoint-Related Genes (ICRGs) were associated with TIME formation.•ICRGs were associated with the prognosis of PAAD.•ICRGs may serve as novel clinical biomarkers and therapeutic targets. To comprehensively analyze the clinical significance of Immune Checkpoint-Related Genes (ICRGs) in Pancreatic Adenocarcinoma (PAAD). PAAD tissues and normal pancreatic tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and 283 ICRGs were integrated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome datasets. Unsupervised clustering was used to obtain potential ICRGs-based PAAD subtypes. Wilcoxon test was performed to screen Differentially Expressed ICRGs (DEICRGs), while cox regression analyses were utilized to identify prognosis-related ICRGs and clinicopathological factors, and construct the corresponding models. The Tumor Immune Microenvironment (TIME) was evaluated. Moreover, the authors performed enrichment analysis, Gene Set Enrichment Analysis (GSEA), and transcription factor regulatory networks to realize underlying mechanisms. Three ICRGs-based PAAD subtypes were identified, and they were associated with three ESTIMATE scores, a Tumor Microenvironment (TMB) score, 14 therapeutic immune checkpoints, and infiltration levels of seven immune cells. On top of that, the authors constructed two signatures based on DEICRGs to predict the Overall Survival (OS) (Area Under the ROC Curve [AUC: 0.741∼0.778]) and Progression-Free Survival (PFS) (AUC: 0.746∼0.831) of patients. Two nomograms were established by combining clinical variables and signatures. In addition, the authors found higher infiltration of naïve B cells and CD8+ T-cells in low-risk PAAD patients, and higher infiltration of suppressive immune cells and cancer-related signaling pathways in high-risk PAAD patients. The present study suggested that ICRGs were associated with TIME formation and prognosis of PAAD patients, which may serve as novel clinical biomarkers and therapeutic targets.