J Cancer 2020; 11(22):6530-6544. doi:10.7150/jca.47877 This issue
1. Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China.
2. Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China.
Background: Pancreatic cancer (PC) is an aggressive cancer with worse survival in the world. Emerging evidence suggested that the imbalance of alternative splicing (AS) is a hallmark of cancer and indicated poor prognosis of patients. Genes-derived splicing events can produce neoepitopes for immunotherapy. However, the profound study of splicing profiling in PC is still elusive. We aimed to identification of novel prognostic signature across a comprehensive splicing landscape and reveal their relationship with tumor-infiltrating immune cells in pancreatic cancer microenvironment.
Methods: Based on integrated analysis of splicing profiling and clinical data, differentially splicing events were filtered out. Then, stepwise Cox regression analysis was applied to identify survival-related splicing events and construct prognostic signature. Functional enrichment analysis was performed to explore biology function. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were performed to validate the predictive effect of predictive signature. We also verified the clinical value of prognostic signature under the influence of different clinical parameters. For deeper analysis, we evaluated the correlation between prognostic signature and infiltrating immune cells by CIBERSORT.
Results: According to systematic analyzing, a final six splicing events were identified and validated the good prognostic capability in entire TCGA dataset, validation set 1 and validation set 2 by Kaplan-Meier curves (P < 0.0001). The area under the curve (AUC) of ROC curves were also confirmed the high predictive efficiency of the prognostic signature in these three cohorts (AUC = 0.857, 0.895 and 0.788). In order to validate whether prognostic signature highlights a correlation between AS and immune contexture, CIBERSORT was performed to analyze the proportion of tumor-infiltrating immune cells in PC. Based on prognostic signature, we identified survival-related immune cells including CD8 T cells (P = 0.0111), activated CD4 memory T cells (P = 0.0329) and resting mast cells (P = 0.0352).
Conclusion: In conclusion, our study contribute to provide a promising prognostic signature based on six splicing events and revealed prognosis-related immune cells which indeed represented novel tumor drivers and provide potential targets for personalized therapeutic.
Keywords: pancreatic cancer, alternative splicing, immune cells infiltration, prognosis, target therapy