新抗原研究的最新进展加速了胶质母细胞瘤（GBM）等癌症免疫疗法的发展。基因组突变和选择性剪接失调产生的新抗原已在 GBM 中进行了研究。然而，这些研究主要集中在带注释的选择性剪接转录本上，而未带注释的转录本基本上未被探索。肿瘤中异常调节的环状核糖核酸（circRNA）与具有外显子跳跃事件的未注释线性转录本的存在相关。但这些线性转录本真正存在的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 circRNA 生物发生和选择性剪接在各种肿瘤类型中普遍存在，从而产生大量的长程选择性剪接转录本 (LR)。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 中震动蛋白的上调，据报道该蛋白可促进 circRNA 生物发生。我们总共鉴定出了 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 种主要组织相容性复合物 I 类相关肽被确定为 GBM 的潜在免疫治疗靶点。这项研究揭示了 GBM 中特异性上调的长程选择性剪接转录物可能作为复发性免疫原性肿瘤特异性抗原。© 作者 2024。由牛津大学出版社出版。

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.© The Author(s) 2024. Published by Oxford University Press.