A novel immune checkpoint score system for prognostic evaluation in pancreatic adenocarcinoma

Abstract Pancreatic adenocarcinoma (PAAD) remains a lethal malignancy making the detection of novel prognostic biomarkers urgent. Limited studies have investigated the predictive capability of immune checkpoints in PAAD. Here, we presented a risk score system based on three immune checkpoints (OX40/TNFRSF4, TNFSF14 and KIR3DL1) through LASSO and Cox regression analyses for prognostic prediction. The risk score model was an independent prognostic factor and performed well regarding overall survival (OS) predictions among PAAD patients. A nomogram was established to facilitate the risk model application in clinical prognosis. Immune cells including naive B cells, CD8 + T cells and Tregs were negatively correlated with the risk score. Additionally, the risk score was associated with expression of immune checkpoint genes, immunogenic cell death related genes and somatic mutations. Glycolysis processes, IL-2-STAT5, IL-6-STAT3, and mTORC1 signaling pathways were enriched in the high-risk score group. Furthermore, scRNA-seq data confirmed that TNFRSF4, TNFSF14 and KIR3DL1 were expressed on immune cells in PAAD samples. We then identified OX40 as an independent prognosis-related gene, and a higher OX40 expression was associated with increased survival rate and immune environment change. In 84 PAAD clinical specimens collected from our center, we confirmed that higher OX40 mRNA expression levels were related to a good prognosis. The protein expression of OX40 on tumor-infiltrating immune cells (TIICs), endothelial cells and tumor cells was verified in PAAD tissues by immunohistochemistry (IHC) method. Overall, our findings strongly suggested that the three-immune checkpoint score system might be useful in the prognosis and design of personalized treatments for PAAD patients. Finally, we identified OX40 as an independent potential biomarker for PAAD prognosis prediction.