Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy.
Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy.
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泛癌症分析揭示了与检查点免疫疗法引起的免疫相关不良事件相关的选择性剪接特征
DOI：
10.3389/fphar.2021.797852
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发表时间：
2021
影响因子：
5.6
通讯作者：
Shi H
中科院分区：
文献类型：
--
作者：
He X;Yu J;Shi H
免疫相关不良事件（irAE）会损害免疫检查点抑制剂（ICI）的有效性和安全性，并限制ICI在肿瘤学中的临床应用。irAE的预测性生物标志物对于早期诊断和后续管理是迫切需要的。irAE的确切机制仍有待充分阐明，预测性生物标志物的可用性有限。在此，我们通过结合药物警戒数据和泛癌症转录组学信息进行数据挖掘，以说明选择性剪接特征与ICI的irAE风险之间的关系。四个不同类别的剪接特征被认为与剪接因子，新抗原，剪接异构体，和剪接水平。相关性分析证实剪接因子的表达水平可预测irAE的风险。将DHX 16表达添加到双变量PD-L1蛋白表达-fPD 1模型中显著增强了对irAE的预测。此外，我们根据irAE发生率与剪接频率和亚型表达的相关性，分别确定了668和1，131个潜在的预测因子。功能分析表明，选择性剪接可能通过协调先天免疫和获得性免疫参与irAE的发病机制。值得注意的是，自身免疫相关基因和自身抗原在这些irAE预测因子中优先过度表达，表明自身免疫与irAE发生之间存在密切联系。此外，我们建立了一个由CDC 42 EP 3 -206、TMEM 138 -211和IRX 3 -202组成的三变量模型，该模型可以更好地预测各种癌症类型中irAE的风险，表明作为irAE的有希望的生物标志物的潜在应用。我们的研究不仅强调了检查点免疫治疗期间选择性剪接与irAE发展的临床相关性，而且还揭示了irAE的潜在机制。
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.
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影响因子：
28.4
作者：
Lee, Joo Sang;Ruppin, Eytan
通讯作者：
Ruppin, Eytan
影响因子：
14.2
作者：
Ng, B;Yang, F;Yang, XF
通讯作者：
Yang, XF
影响因子：
6.2
作者：
Kelly K;Infante JR;Taylor MH;Patel MR;Wong DJ;Iannotti N;Mehnert JM;Loos AH;Koch H;Speit I;Gulley JL
通讯作者：
Gulley JL
影响因子：
50.3
作者：
Kahles, Andre;Lehmann, Kjong-Van;Ratsch, Gunnar
通讯作者：
Ratsch, Gunnar
影响因子：
158.5
作者：
Lee, Eun Bong;Fleischmann, Roy;van Vollenhoven, Ronald F.
通讯作者：
van Vollenhoven, Ronald F.