Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma

Autor: Yi Wang, Gang Chen, Bangjie He, Tuo Deng, Liming Deng, Bo Chen, Daojie Wang, Chongming Zheng, Haitao Yu, Kaiyu Chen
Rok vydání: 2021
Předmět:
CD4-Positive T-Lymphocytes
Male
Cancer Research
B7 Antigens
medicine.medical_treatment
Kaplan-Meier Estimate
CD8-Positive T-Lymphocytes
medicine.disease_cause
T-Lymphocytes
Regulatory
B7-H1 Antigen
Tumor Microenvironment
Cytotoxic T cell
RC254-282
Immunity
Cellular
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Middle Aged
Prognosis
Tumour immune microenvironment
Oncology
Receptors
Virus
Adenocarcinoma
Female
RNA Splicing Factors
Immunotherapy
Algorithms
Carcinoma
Pancreatic Ductal
CD47 Antigen
Immune system
Genetics
medicine
Humans
Survival analysis
Aged
Proportional Hazards Models
business.industry
Research
Nomogram
Immune Checkpoint Proteins
medicine.disease
Immune checkpoint
Pancreatic Neoplasms
Nomograms
Mutation
Cancer research
business
Carcinogenesis
Pancreatic adenocarcinoma
Alternative splicing
Zdroj: BMC Cancer
BMC Cancer, Vol 21, Iss 1, Pp 1-16 (2021)
ISSN: 1471-2407
Popis: Purpose Pancreatic adenocarcinoma (PAAD) is characterized by low antitumour immune cell infiltration in an immunosuppressive microenvironment. This study aimed to systematically explore the impact on prognostic alternative splicing events (ASs) of tumour immune microenvironment (TIME) in PAAD. Methods The ESTIMATE algorithm was implemented to compute the stromal/immune-related scores of each PAAD patient, followed by Kaplan–Meier (KM) survival analysis of patients with different scores grouped by X-tile software. TIME-related differentially expressed ASs (DEASs) were determined and evaluated through functional annotation analysis. In addition, Cox analyses were implemented to construct a TIME-related signature and an AS clinical nomogram. Moreover, comprehensive analyses, including gene set enrichment analysis (GSEA), immune infiltration, immune checkpoint gene expression, and tumour mutation were performed between the two risk groups to understand the potential mechanisms. Finally, Cytoscape was implemented to illuminate the AS-splicing factor (SF) regulatory network. Results A total of 437 TIME-related DEASs significantly related to PAAD tumorigenesis and the formation of the TIME were identified. Additionally, a robust TIME-related prognostic signature based on seven DEASs was generated, and an AS clinical nomogram combining the signature and four clinical predictors also exhibited prominent discrimination by ROC (0.762 ~ 0.804) and calibration curves. More importantly, the fractions of CD8 T cells, regulatory T cells and activated memory CD4 T cells were lower, and the expression of four immune checkpoints—PD-L1, CD47, CD276, and PVR—was obviously higher in high-risk patients. Finally, functional analysis and tumour mutations revealed that aberrant immune signatures and activated carcinogenic pathways in high-risk patients may be the cause of the poor prognosis. Conclusion We extracted a list of DEASs associated with the TIME through the ESTIMATE algorithm and constructed a prognostic signature on the basis of seven DEASs to predict the prognosis of PAAD patients, which may guide advanced decision-making for personalized precision intervention.
Databáze: OpenAIRE
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