Techachakrit Jirapat, Malik Aijaz Ahmad, Pisitkun Trairak, Sriswasdi Sira
Center of Excellence in Computational Molecular Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Sci Rep. 2025 May 7;15(1):15886. doi: 10.1038/s41598-025-00817-6.
Isoform switching in cancer is a prevalent phenomenon with significant implications for immunotherapy, as actionable neoantigens derived from these cancer-specific events would be applicable to broad categories of patients, reducing the necessity for personalized treatments. By integrating five large-scale transcriptomic datasets comprising over 19,500 samples across 29 cancer and 54 normal tissue types, we identified cancer-associated isoform switching events common to multiple cancer types, several of which involve genes with established mechanistic roles in oncogenesis. The presence of neoantigen-containing peptides derived from these transcripts was confirmed in broad cancer and normal tissue proteome datasets and the binding affinity of predicted neoantigens to the human leukocyte antigen (HLA) complex via molecular dynamics simulations. The study presents strong evidence that isoform switching in cancer is a significant source of actionable neoantigens that have the capability to trigger an immune response. These findings suggest that isoform switching events could potentially be leveraged for broad immunotherapeutic strategies across various cancer types.
癌症中的异构体转换是一种普遍现象，对免疫治疗具有重要意义，因为源自这些癌症特异性事件的可操作新抗原将适用于广泛类别的患者，从而减少个性化治疗的必要性。通过整合五个大规模转录组数据集，这些数据集包含来自29种癌症和54种正常组织类型的超过19500个样本，我们确定了多种癌症类型共有的癌症相关异构体转换事件，其中一些涉及在肿瘤发生中具有既定机制作用的基因。在广泛的癌症和正常组织蛋白质组数据集中证实了源自这些转录本的含新抗原肽的存在，并通过分子动力学模拟证实了预测新抗原与人白细胞抗原（HLA）复合物的结合亲和力。该研究提供了强有力的证据，表明癌症中的异构体转换是可触发免疫反应的可操作新抗原的重要来源。这些发现表明，异构体转换事件有可能被用于针对各种癌症类型的广泛免疫治疗策略。
