Cancer Immunol Res. 2025 Jun 26. doi: 10.1158/2326-6066.CIR-24-0091. Online ahead of print.
ABSTRACT
Acquired mutations in spliceosome genes in early hematopoietic stem/progenitor cells are common events in myelodysplastic neoplasms (MDS) and related myeloid malignancies. Mutations in the spliceosome factor subunit B1 (SF3B1) gene occur in ≥20% of MDS cases at conserved hotspots and in early neoplastic clones as driver events. Neoantigens from aberrant SF3B1 proteins could serve as shared T-cell therapy targets for SF3B1-mutated myeloid neoplasms. We identified a candidate neoantigen from the prevalent SF3B1K700E variant using in silico predictions of epitope processing and presentation, then validated presentation and immunogenicity in vitro. CD8+ T cells recognizing SF3B1K700E demonstrated high functional avidity and killed neoplastic myeloid cell lines and primary cells in an antigen-specific manner. We then sequenced, cloned, and transduced a SF3B1K700E-specific T-cell receptor (TCR) into 3rd-party T cells and confirmed that TCR transfer conferred antigen specificity and killing of neoplastic myeloid cells in vitro and in vivo. The data indicate that the SF3B1K700E neoantigen represents a promising T-cell target for patients with SF3B1-mutated MDS and acute myeloid leukemia.
PMID:40569290 | DOI:10.1158/2326-6066.CIR-24-0091