Long-range alternative splicing contributes to neoantigen specificity in glioblastoma.

IF 6.8 2区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS
Mingjun Ji, Qing Yu, Xin-Zhuang Yang, Xianhong Yu, Jiaxin Wang, Chunfu Xiao, Ni A An, Chuanhui Han, Chuan-Yun Li, Wanqiu Ding
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Abstract

Recent advances in neoantigen research have accelerated the development of immunotherapies for cancers, such as glioblastoma (GBM). Neoantigens resulting from genomic mutations and dysregulated alternative splicing have been studied in GBM. However, these studies have primarily focused on annotated alternatively-spliced transcripts, leaving non-annotated transcripts largely unexplored. Circular ribonucleic acids (circRNAs), abnormally regulated in tumors, are correlated with the presence of non-annotated linear transcripts with exon skipping events. But the extent to which these linear transcripts truly exist and their functions in cancer immunotherapies remain unknown. Here, we found the ubiquitous co-occurrence of circRNA biogenesis and alternative splicing across various tumor types, resulting in large amounts of long-range alternatively-spliced transcripts (LRs). By comparing tumor and healthy tissues, we identified tumor-specific LRs more abundant in GBM than in normal tissues and other tumor types. This may be attributable to the upregulation of the protein quaking in GBM, which is reported to promote circRNA biogenesis. In total, we identified 1057 specific and recurrent LRs in GBM. Through in silico translation prediction and MS-based immunopeptidome analysis, 16 major histocompatibility complex class I-associated peptides were identified as potential immunotherapy targets in GBM. This study revealed long-range alternatively-spliced transcripts specifically upregulated in GBM may serve as recurrent, immunogenic tumor-specific antigens.

长程替代剪接有助于胶质母细胞瘤新抗原特异性的形成。
新抗原研究的最新进展加速了胶质母细胞瘤(GBM)等癌症免疫疗法的开发。人们已经对 GBM 中基因组突变和替代剪接失调产生的新抗原进行了研究。然而,这些研究主要集中在有注释的另类剪接转录本上,对无注释的转录本基本上没有进行研究。肿瘤中异常调控的环状核糖核酸(circRNA)与存在外显子跳过事件的非注释线性转录本相关。但这些线性转录本的真实存在程度及其在癌症免疫疗法中的功能仍然未知。在这里,我们发现在各种肿瘤类型中,circRNA的生物发生和替代剪接无处不在,从而产生了大量的长程替代剪接转录本(LRs)。通过比较肿瘤组织和健康组织,我们发现肿瘤特异性 LRs 在 GBM 中比在正常组织和其他肿瘤类型中更为丰富。这可能归因于 GBM 中蛋白 quaking 的上调,有报道称这种蛋白能促进 circRNA 的生物生成。我们在 GBM 中总共发现了 1057 个特异性和复发性 LRs。通过硅翻译预测和基于 MS 的免疫肽组分析,我们发现 16 种主要组织相容性复合体 I 类相关肽是 GBM 中潜在的免疫治疗靶点。这项研究揭示了在GBM中特异性上调的长程交替剪接转录本可作为复发性、免疫原性肿瘤特异性抗原。
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来源期刊
Briefings in bioinformatics
Briefings in bioinformatics 生物-生化研究方法
CiteScore
13.20
自引率
13.70%
发文量
549
审稿时长
6 months
期刊介绍: Briefings in Bioinformatics is an international journal serving as a platform for researchers and educators in the life sciences. It also appeals to mathematicians, statisticians, and computer scientists applying their expertise to biological challenges. The journal focuses on reviews tailored for users of databases and analytical tools in contemporary genetics, molecular and systems biology. It stands out by offering practical assistance and guidance to non-specialists in computerized methodologies. Covering a wide range from introductory concepts to specific protocols and analyses, the papers address bacterial, plant, fungal, animal, and human data. The journal's detailed subject areas include genetic studies of phenotypes and genotypes, mapping, DNA sequencing, expression profiling, gene expression studies, microarrays, alignment methods, protein profiles and HMMs, lipids, metabolic and signaling pathways, structure determination and function prediction, phylogenetic studies, and education and training.
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