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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Published in:Cell Vol. 188; no. 13; p. 3422
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 26.06.2025
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2025.03.047