Tumour-wide RNA splicing aberrations generate actionable public neoantigens

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

Nature, 2025, vol. 639, issue 8054, 463-473

Abstract: 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 heterogeneity2–4. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08552-0

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