Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias.

Publication Type	Academic Article
Authors	Kim W, Crosse E, De Neef E, Etxeberria I, Sabio E, Wang E, Bewersdorf J, Lin K, Lu S, Belleville A, Fox N, Castro C, Zhang P, Fujino T, Lewis J, Rahman J, Zhang B, Winick J, Lewis A, Stanley R, DeWolf S, Urben B, Takizawa M, Krause T, Molina H, Chaligne R, Koppikar P, Molldrem J, Gigoux M, Merghoub T, Daniyan A, Chandran S, Greenbaum B, Klebanoff C, Bradley R, Abdel-Wahab O
Journal	Cell
Volume	188
Issue	13
Pagination	3422-3440.e24
Date Published	04/23/2025
ISSN	1097-4172
Keywords	Receptors, Antigen, T-Cell, RNA Splicing, Antigens, Neoplasm, RNA Splicing Factors, Leukemia
Abstract	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+ 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.
DOI	10.1016/j.cell.2025.03.047
PubMed ID	40273911
PubMed Central ID	PMC12204805