期刊
CANCER DISCOVERY
卷 11, 期 8, 页码 1938-1951出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0555
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资金
- Agence Nationale de la Recherche [ANR10EQPX03, ANR10INBS0908]
- Canceropole Ile-de-France
- SiRIC Curie program
- European Union [667787]
- Ligue Nationale Contre le Cancer
- Institut Curie
- Institut National de la Sante et de la Recherche Medicale
- ANR
- ARC fondation
- INCA
- Labex DCBIOL, Canceropole Ile de France emergence, SIRIC
- Region Ile-deFrance
- Fondation pour la Recherche Medicale
Mutations in the splicing factor SF3B1 in uveal melanoma generate immunogenic neoantigens that can be recognized and killed by specific CD8(+) T cells, providing a potential new therapeutic target for tumors. These findings suggest that mutations in splicing factors may be a valuable source for developing novel therapeutic strategies for various types of cancers.
Disruption of splicing patterns due to mutations of genes coding splicing factors in tumors represents a potential source of tumor neoantigens, which would be both public (shared between patients) and tumor-specific (not expressed in normal tissues). In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma generate such immunogenic neoantigens. Memory CD8(+) T cells specific for these neoantigens are preferentially found in 20% of patients with uveal melanoma bearing SF3B1-mutated tumors. Single-cell analyses of neoepitope-specific T cells from the blood identified large clonal T-cell expansions, with distinct effector transcription patterns. Some of these expanded T-cell receptors are also present in the corresponding tumors. CD8(+) T-cell clones specific for the neoepitopes specifically recognize and kill SF3B1-mutated tumor cells, supporting the use of this new family of neoantigens as therapeutic targets. SIGNIFICANCE: Mutations of the splicing factor SF3B1 in uveal melanoma generate shared neoantigens that are uniquely expressed by tumor cells, leading to recognition and killing by specific CD8 T cells. Mutations in splicing factors can be sources of new therapeutic strategies applicable to diverse tumors.
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