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 muta...

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Vydáno v:	Cell Ročník 188; číslo 13; s. 3422
Hlavní autoři:	Kim, Won Jun, Crosse, Edie I, De Neef, Emma, Etxeberria, Inaki, Sabio, Erich Y, Wang, Eric, Bewersdorf, Jan Philipp, Lin, Kuan-Ting, Lu, Sydney X, Belleville, Andrea, Fox, Nina, Castro, Cynthia, Zhang, Pu, Fujino, Takeshi, Lewis, Jennifer, Rahman, Jahan, Zhang, Beatrice, Winick, Jacob H, Lewis, Alexander M, Stanley, Robert F, DeWolf, Susan, Urben, Brigita Meškauskaitė, Takizawa, Meril, Krause, Tobias, Molina, Henrik, Chaligne, Ronan, Koppikar, Priya, Molldrem, Jeffrey, Gigoux, Mathieu, Merghoub, Taha, Daniyan, Anthony, Chandran, Smita S, Greenbaum, Benjamin D, Klebanoff, Christopher A, Bradley, Robert K, Abdel-Wahab, Omar
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 26.06.2025
Témata:	Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology CD8-Positive T-Lymphocytes - immunology Humans Leukemia - genetics Leukemia - immunology Mutation Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - immunology Receptors, Antigen, T-Cell - metabolism RNA Splicing - genetics RNA Splicing Factors - genetics Serine-Arginine Splicing Factors - genetics neoantigen ZRSR2 T cell receptor acute myeloid leukemia immunotherapy myelodysplastic syndromes SRSF2 U2AF1 SF3B1 RNA splicing
ISSN:	1097-4172, 1097-4172
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2025.03.047