Tumour-wide RNA splicing aberrations generate actionable public neoantigens

Darwin Kwok(University of California, San Francisco), Nicholas Stevers(University of California, San Francisco), Iñaki Etxeberría(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 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 Grishanina(University of California, San Francisco), James Woo(University of California, San Francisco), Aarón Díaz(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), J Costello(University of California, San Francisco), Hideho Okada(University of California, San Francisco)
Nature
February 19, 2025
10.1038/s41586-024-08552-0
Cited by 61Open Access
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Abstract

Abstract T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens 1 . However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity 2–4 . 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.

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