长程可变剪接在胶质母细胞瘤新抗原特异性中的贡献
Long-range alternative splicing contributes to neoantigen specificity in glioblastoma
DOI 原文链接
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影响因子:7.7
分区:生物学2区 / 数学与计算生物学1区 生化研究方法2区
发表日期:2024 Sep 23
作者:
Mingjun Ji, Qing Yu, Xin-Zhuang Yang, Xianhong Yu, Jiaxin Wang, Chunfu Xiao, Ni A An, Chuanhui Han, Chuan-Yun Li, Wanqiu Ding
DOI:
10.1093/bib/bbae503
摘要
新抗原研究的最新进展加速了癌症免疫疗法的发展，如胶质母细胞瘤（GBM）。由基因组突变和失调的可变剪接产生的新抗原已在GBM中得到研究。然而，这些研究主要关注已注释的可变剪接转录本，非注释转录本尚未得到充分探索。环状核糖核酸（circRNA）在肿瘤中的异常调控，与非注释线性转录本（伴有外显子跳跃事件）的出现相关联。但这些线性转录本的真实存在程度及其在癌症免疫治疗中的作用仍未知。本研究发现circRNA的生物合成与多种肿瘤类型中的可变剪接普遍共现，产生大量长程可变剪接转录本（LRs）。通过比较肿瘤组织与健康组织，识别出在GBM中更丰富的肿瘤特异性LRs，可能与GBM中蛋白质quaking的上调有关，后者已被报道促进circRNA的生物合成。总共鉴定出1057个GBM特异性且反复出现的LRs。通过体外翻译预测和质谱免疫肽组分析，鉴定出16个主要组织相容性抗原（MHC-I）相关肽，作为潜在的免疫治疗靶点。本研究揭示，GBM中特异性上调的长程可变剪接转录本可能作为反复出现的、具有免疫原性的肿瘤特异性抗原。
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.