美国加州大学Hideho Okada研究小组揭示了肿瘤范围内的RNA剪接畸变产生可操作的公共新抗原。该研究于2025年2月19日发表于国际一流学术期刊《自然》杂志上。

在这里，该研究组介绍了一类以前未被表征的肿瘤范围内的公共新抗原，它们起源于不同癌症类型的RNA剪接畸变。课题组研究人员发现了能够识别和靶向GNAS和RPL22中异常剪接产生的新抗原的T细胞受体克隆。在多部位活检的病例中，该研究团队检测到了GNAS新结在胶质瘤、间皮瘤、前列腺癌和肝癌中的全肿瘤表达。这些新抗原是肿瘤细胞在生理条件下内源性产生和呈递的，足以触发新抗原特异性CD8⁺ T细胞消灭癌细胞。

此外，他们的研究强调了剪接因子表达失调在特定癌症类型中的作用，导致新连接上调的复发模式。这些发现为T细胞免疫疗法解决细胞内异质性的挑战奠定了分子基础。

据了解，基于T细胞的免疫疗法通过利用免疫系统对癌症特异性抗原的识别，有望治疗癌症。然而，它们在体细胞突变少、瘤内异质性大的肿瘤中疗效有限。

附：英文原文

Title: Tumour-wide RNA splicing aberrations generate actionable public neoantigens

Author: Kwok, Darwin W., Stevers, Nicholas O., Etxeberria, Iaki, Nejo, Takahide, Colton Cove, Maggie, Chen, Lee H., Jung, Jangham, Okada, Kaori, Lakshmanachetty, Senthilnath, Gallus, Marco, Barpanda, Abhilash, Hong, Chibo, Chan, Gary K. L., Liu, Jerry, Wu, Samuel H., Ramos, Emilio, Yamamichi, Akane, Watchmaker, Payal B., Ogino, Hirokazu, Saijo, Atsuro, Du, Aidan, Grishanina, Nadia R., Woo, James, Diaz, Aaron, Hervey-Jumper, Shawn L., Chang, Susan M., Phillips, Joanna J., Wiita, Arun P., Klebanoff, Christopher A., Costello, Joseph F., Okada, Hideho

Issue&Volume: 2025-02-19

Abstract: T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens1. However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity2,3,4. Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cells under physiologic conditions and are sufficient to trigger cancer cell eradication by neoantigen-specific CD8⁺ Tcells. Moreover, our study highlights a role for dysregulated splicing factor expression in specific cancer types, leading to recurrent patterns of neojunction upregulation. These findings establish a molecular basis for T cell-based immunotherapies addressing the challenges of intratumoural heterogeneity.

DOI: 10.1038/s41586-024-08552-0

Source: https://www.nature.com/articles/s41586-024-08552-0