Tumour-wide RNA splicing aberrations generate actionable public neoantigens Journal Article
| Authors: | Kwok, D. W.; Stevers, N. O.; Etxeberria, I.; Nejo, T.; Colton Cove, M.; Chen, L. H.; Jung, J.; Okada, K.; Lakshmanachetty, S.; Gallus, M.; Barpanda, A.; Hong, C.; Chan, G. K. L.; Liu, J.; Wu, S. H.; Ramos, E.; Yamamichi, A.; Watchmaker, P. B.; Ogino, H.; Saijo, A.; Du, A.; Grishanina, N. R.; Woo, J.; Diaz, A.; Hervey-Jumper, S. L.; Chang, S. M.; Phillips, J. J.; Wiita, A. P.; Klebanoff, C. A.; Costello, J. F.; Okada, H. |
| Article Title: | Tumour-wide RNA splicing aberrations generate actionable public neoantigens |
| 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+ T cells. 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. © The Author(s) 2025. |
| Keywords: | controlled study; human tissue; unclassified drug; human cell; genetics; flow cytometry; glioma; neoplasm; neoplasms; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; metabolism; animals; mice; cell viability; dendritic cell; interleukin 21; interleukin 4; interleukin 7; cell line, tumor; tumor antigen; renal cell carcinoma; genetic transduction; prostate cancer; rna; immunology; immune response; antigen; immunotherapy; antigens, neoplasm; receptors, antigen, t-cell; tumor cell line; mesothelioma; liver cancer; prostate adenocarcinoma; tumor; stomach adenocarcinoma; colon adenocarcinoma; therapy; hla antigen; lymphocyte antigen receptor; rna splicing; physiological response; liquid chromatography-mass spectrometry; spectrophotometry; gene knockdown; cellular immunotherapy; cell component; cancer; humans; human; male; female; article; gene set enrichment analysis; neoantigen; hek293t cell line; thp-1 cell line; real time reverse transcription polymerase chain reaction; single cell rna seq; enterobacteria phage t7; small nuclear ribonucleoprotein d2 polypeptide; splicing factor 3asubunit 3; cos-7 cell line; t2 cell line (lymphoblastoid) |
| Journal Title: | Nature |
| Volume: | 639 |
| Issue: | 8054 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-03-13 |
| Start Page: | 463 |
| End Page: | 473 |
| Language: | English |
| DOI: | 10.1038/s41586-024-08552-0 |
| PUBMED: | 39972144 |
| PROVIDER: | scopus |
| PMCID: | PMC11903331 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Christopher Klebanoff -- Source: Scopus |
