Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias
Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8<sup>+</sup> T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.
Authors
- Nina Fox
- Kuan‐Ting Lin (ORCID: https://orcid.org/0000-0003-1294-1142)
- Taha Merghoub (ORCID: https://orcid.org/0000-0002-1518-5111)
- Meril Takizawa
- Smita S. Chandran (ORCID: https://orcid.org/0000-0001-9266-6878)
- Edie I. Crosse (ORCID: https://orcid.org/0000-0002-0477-7365)
- Jennifer Lewis (ORCID: https://orcid.org/0009-0009-9619-9731)
- Omar Abdel‐Wahab (ORCID: https://orcid.org/0000-0002-3907-6171)
- Henrik Molina (ORCID: https://orcid.org/0000-0001-8950-4990)
- Takeshi Fujino (ORCID: https://orcid.org/0000-0001-5862-1203)
- Mathieu Gigoux (ORCID: https://orcid.org/0000-0002-1831-7597)
- Andrea E. Belleville (ORCID: https://orcid.org/0000-0001-9549-4338)
- Erich Sabio (ORCID: https://orcid.org/0000-0001-9310-8042)
- Susan DeWolf (ORCID: https://orcid.org/0000-0002-2754-3537)
- Robert K. Bradley (ORCID: https://orcid.org/0000-0002-8046-1063)
- Won Jun Kim (ORCID: https://orcid.org/0000-0002-1816-6119)
- Jeffrey D. Winick
- Sydney X. Lu (ORCID: https://orcid.org/0000-0002-2217-1674)
- Jeffrey J. Molldrem (ORCID: https://orcid.org/0000-0003-1196-1715)
- Anthony F. Daniyan (ORCID: https://orcid.org/0009-0002-2742-2281)
- Priya Koppikar (ORCID: https://orcid.org/0000-0002-4966-5826)
- Benjamin D. Greenbaum (ORCID: https://orcid.org/0000-0001-6153-8793)
- Emma De Neef
- Beatrice Zhang (ORCID: https://orcid.org/0000-0003-1636-600X)
- Iñaki Etxeberría (ORCID: https://orcid.org/0000-0003-2713-0836)
- Christopher A. Klebanoff (ORCID: https://orcid.org/0000-0001-9645-3896)
- Jahan Rahman (ORCID: https://orcid.org/0000-0001-8755-5890)
- Jan Philipp Bewersdorf (ORCID: https://orcid.org/0000-0003-3352-0902)
- Brigita Meškauskaitė Urben
- Pu Zhang (ORCID: https://orcid.org/0000-0003-4174-8202)
- Eric Wang (ORCID: https://orcid.org/0000-0001-7865-6702)
- Robert F. Stanley (ORCID: https://orcid.org/0000-0003-3643-8592)
- Alexander M. Lewis (ORCID: https://orcid.org/0000-0001-8003-9535)
- Cynthia Castro (ORCID: https://orcid.org/0009-0002-7626-8903)
- Tobias Krause
- Ronan Chaligné (ORCID: https://orcid.org/0000-0001-5788-5848)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cornell University (US)
- Swim Across America (US)
- Kettering University (US)
- Fred Hutch Cancer Center (US)
- HiFiBiO Therapeutics (United States) (US)
- Parker Institute for Cancer Immunotherapy (US)
- Jackson Laboratory (US)
- Rockefeller University (US)
- Singer (United States) (US)
- Stanford University (US)
Publication Details
- Journal
- Cell
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1016/j.cell.2025.03.047
- Citations
- 27
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 21.76