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

Abstract 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 PA...

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Autores principales:	Bo Chen, Tuo Deng, Liming Deng, Haitao Yu, Bangjie He, Kaiyu Chen, Chongming Zheng, Daojie Wang, Yi Wang, Gang Chen
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Pancreatic adenocarcinoma Alternative splicing Tumour immune microenvironment Prognosis Immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2781bfa6e1b94e988544a1cda935e6f9
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spelling	oai:doaj.org-article:2781bfa6e1b94e988544a1cda935e6f92021-11-14T12:30:11ZIdentification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma10.1186/s12885-021-08962-71471-2407https://doaj.org/article/2781bfa6e1b94e988544a1cda935e6f92021-11-01T00:00:00Zhttps://doi.org/10.1186/s12885-021-08962-7https://doaj.org/toc/1471-2407Abstract 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.Bo ChenTuo DengLiming DengHaitao YuBangjie HeKaiyu ChenChongming ZhengDaojie WangYi WangGang ChenBMCarticlePancreatic adenocarcinomaAlternative splicingTumour immune microenvironmentPrognosisImmunotherapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBMC Cancer, Vol 21, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pancreatic adenocarcinoma Alternative splicing Tumour immune microenvironment Prognosis Immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Pancreatic adenocarcinoma Alternative splicing Tumour immune microenvironment Prognosis Immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Bo Chen Tuo Deng Liming Deng Haitao Yu Bangjie He Kaiyu Chen Chongming Zheng Daojie Wang Yi Wang Gang Chen Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
description	Abstract 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.
format	article
author	Bo Chen Tuo Deng Liming Deng Haitao Yu Bangjie He Kaiyu Chen Chongming Zheng Daojie Wang Yi Wang Gang Chen
author_facet	Bo Chen Tuo Deng Liming Deng Haitao Yu Bangjie He Kaiyu Chen Chongming Zheng Daojie Wang Yi Wang Gang Chen
author_sort	Bo Chen
title	Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
title_short	Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
title_full	Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
title_fullStr	Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
title_full_unstemmed	Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
title_sort	identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/2781bfa6e1b94e988544a1cda935e6f9
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Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma

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