Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy

Immune-related adverse events (irAEs) can impair the effectiveness and safety of immune checkpoint inhibitors (ICIs) and restrict the clinical applications of ICIs in oncology. The predictive biomarkers of irAE are urgently required for early diagnosis and subsequent management. The exact mechanism...

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Autores principales:	Xiujing He, Jing Yu, Hubing Shi
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	immune-related adverse events immune checkpoint inhibitors cancer immunotherapy alternative splicing splicing isoforms Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/25a5360c76b84b09966f0ca0586bfb3e
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spelling	oai:doaj.org-article:25a5360c76b84b09966f0ca0586bfb3e2021-11-30T17:59:47ZPan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy1663-981210.3389/fphar.2021.797852https://doaj.org/article/25a5360c76b84b09966f0ca0586bfb3e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.797852/fullhttps://doaj.org/toc/1663-9812Immune-related adverse events (irAEs) can impair the effectiveness and safety of immune checkpoint inhibitors (ICIs) and restrict the clinical applications of ICIs in oncology. The predictive biomarkers of irAE are urgently required for early diagnosis and subsequent management. The exact mechanism underlying irAEs remains to be fully elucidated, and the availability of predictive biomarkers is limited. Herein, we performed data mining by combining pharmacovigilance data and pan-cancer transcriptomic information to illustrate the relationships between alternative splicing characteristics and irAE risk of ICIs. Four distinct classes of splicing characteristics considered were associated with splicing factors, neoantigens, splicing isoforms, and splicing levels. Correlation analysis confirmed that expression levels of splicing factors were predictive of irAE risk. Adding DHX16 expression to the bivariate PD-L1 protein expression-fPD1 model markedly enhanced the prediction for irAE. Furthermore, we identified 668 and 1,131 potential predictors based on the correlation of the incidence of irAEs with splicing frequency and isoform expression, respectively. The functional analysis revealed that alternative splicing might contribute to irAE pathogenesis via coordinating innate and adaptive immunity. Remarkably, autoimmune-related genes and autoantigens were preferentially over-represented in these predictors for irAE, suggesting a close link between autoimmunity and irAE occurrence. In addition, we established a trivariate model composed of CDC42EP3-206, TMEM138-211, and IRX3-202, that could better predict the risk of irAE across various cancer types, indicating a potential application as promising biomarkers for irAE. Our study not only highlights the clinical relevance of alternative splicing for irAE development during checkpoint immunotherapy but also sheds new light on the mechanisms underlying irAEs.Xiujing HeJing YuHubing ShiFrontiers Media S.A.articleimmune-related adverse eventsimmune checkpoint inhibitorscancer immunotherapyalternative splicingsplicing isoformsTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	immune-related adverse events immune checkpoint inhibitors cancer immunotherapy alternative splicing splicing isoforms Therapeutics. Pharmacology RM1-950
spellingShingle	immune-related adverse events immune checkpoint inhibitors cancer immunotherapy alternative splicing splicing isoforms Therapeutics. Pharmacology RM1-950 Xiujing He Jing Yu Hubing Shi Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy
description	Immune-related adverse events (irAEs) can impair the effectiveness and safety of immune checkpoint inhibitors (ICIs) and restrict the clinical applications of ICIs in oncology. The predictive biomarkers of irAE are urgently required for early diagnosis and subsequent management. The exact mechanism underlying irAEs remains to be fully elucidated, and the availability of predictive biomarkers is limited. Herein, we performed data mining by combining pharmacovigilance data and pan-cancer transcriptomic information to illustrate the relationships between alternative splicing characteristics and irAE risk of ICIs. Four distinct classes of splicing characteristics considered were associated with splicing factors, neoantigens, splicing isoforms, and splicing levels. Correlation analysis confirmed that expression levels of splicing factors were predictive of irAE risk. Adding DHX16 expression to the bivariate PD-L1 protein expression-fPD1 model markedly enhanced the prediction for irAE. Furthermore, we identified 668 and 1,131 potential predictors based on the correlation of the incidence of irAEs with splicing frequency and isoform expression, respectively. The functional analysis revealed that alternative splicing might contribute to irAE pathogenesis via coordinating innate and adaptive immunity. Remarkably, autoimmune-related genes and autoantigens were preferentially over-represented in these predictors for irAE, suggesting a close link between autoimmunity and irAE occurrence. In addition, we established a trivariate model composed of CDC42EP3-206, TMEM138-211, and IRX3-202, that could better predict the risk of irAE across various cancer types, indicating a potential application as promising biomarkers for irAE. Our study not only highlights the clinical relevance of alternative splicing for irAE development during checkpoint immunotherapy but also sheds new light on the mechanisms underlying irAEs.
format	article
author	Xiujing He Jing Yu Hubing Shi
author_facet	Xiujing He Jing Yu Hubing Shi
author_sort	Xiujing He
title	Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy
title_short	Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy
title_full	Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy
title_fullStr	Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy
title_full_unstemmed	Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy
title_sort	pan-cancer analysis reveals alternative splicing characteristics associated with immune-related adverse events elicited by checkpoint immunotherapy
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/25a5360c76b84b09966f0ca0586bfb3e
work_keys_str_mv	AT xiujinghe pancanceranalysisrevealsalternativesplicingcharacteristicsassociatedwithimmunerelatedadverseeventselicitedbycheckpointimmunotherapy AT jingyu pancanceranalysisrevealsalternativesplicingcharacteristicsassociatedwithimmunerelatedadverseeventselicitedbycheckpointimmunotherapy AT hubingshi pancanceranalysisrevealsalternativesplicingcharacteristicsassociatedwithimmunerelatedadverseeventselicitedbycheckpointimmunotherapy
_version_	1718406367811731456

Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy

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