远程替代剪接有助于胶质母细胞瘤的新抗原特异性
Long-range alternative splicing contributes to neoantigen specificity in glioblastoma
影响因子:7.70000
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
摘要
新抗原研究的最新进展加速了癌症（例如胶质母细胞瘤（GBM））的免疫疗法的发展。在GBM中研究了由基因组突变和失调的替代剪接引起的新抗原。但是，这些研究主要集中在注释的替代转录本上，而未经许可的转录本在很大程度上没有探索。在肿瘤中受异常调控的圆核糖酸（CIRCRNA）与存在外显子跳过事件的非宣传线性转录本的存在相关。但是，这些线性转录本真正存在的程度以及它们在癌症免疫疗法中的功能仍然未知。在这里，我们发现ciRCRNA生物发生和各种肿瘤类型的替代剪接无处不在，导致大量的长期替代的转录本（LRS）。通过比较肿瘤和健康组织，我们发现GBM中的肿瘤特异性LR比正常组织和其他肿瘤类型更丰富。这可能归因于GBM中蛋白质颤动的上调，据报道，这促进了circrna生物发生。我们总共确定了GBM中的1057个特异性和复发性LR。通过计算机翻译预测和基于MS的免疫肽组分析，16个主要的组织相容性复合物I类相关肽被确定为GBM中潜在的免疫疗法靶标。这项研究表明，在GBM中特异性上调的远距离转录可能是复发性的免疫原性肿瘤特异性抗原。
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.