A promising natural killer cell-based model and a nomogram for the prognostic prediction of clear-cell renal cell carcinoma

Background: Clear-cell renal cell carcinoma (ccRCC) is one of prevalent kidney malignancies with an unfavorable prognosis. There is a need for a robust model to predict ccRCC patient survival and guide treatment decisions. Methods: RNA-seq data and clinical information of ccRCC were obtained from the TCGA and ICGC databases. Expression profiles of genes related to natural killer (NK) cells were collected from the Immunology Database and Analysis Portal database. Key NK cell-related genes were identified using consensus clustering algorithms to classify patients into distinct clusters. A NK cell-related risk model was then developed using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression to predict ccRCC patient prognosis. The relationship between the NK cell-related risk score and overall survival, clinical features, tumor immune characteristics, as well as response to commonly used immunotherapies and chemotherapy, was explored. Finally, the NK cell-related risk score was validated using decision tree and nomogram analyses. Results: ccRCC patients were stratified into 3 molecular clusters based on expression of NK cell-related genes. Significant differences were observed among the clusters in terms of prognosis, clinical characteristics, immune infiltration, and therapeutic response. Furthermore, six NK cell-related genes (DPYSL3, SLPI, SLC44A4, ZNF521, LIMCH1, and AHR) were identified to construct a prognostic model for ccRCC prediction. The high-risk group exhibited poor survival outcomes, lower immune cell infiltration, and decreased sensitivity to conventional chemotherapies and immunotherapies. Importantly, the quantitative real-time polymerase chain reaction (qRT-PCR) confirmed significantly high DPYSL3 expression and low SLC44A4 expression in ACHN cells. Finally, the decision tree and nomogram consistently show the dramatic prediction performance of the risk score on the survival outcome of the ccRCC patients. Conclusions: The six-gene model based on NK cell-related gene expression was validated and found to accurately mirror immune microenvironment and predict clinical outcomes, contributing to enhanced risk stratification and therapy response for ccRCC patients.