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Splicing Patterns in SF3B1-Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes
Jeremy Bigot1, Ana I Lalanne2,3, Francesca Lucibello1
1INSERM U932, PSL University, Institut Curie, Paris, France.
Abstract:
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.This article is highlighted in the In This Issue feature, p. 1861.
Insights
Mutations in the splicing factor SF3B1 in uveal melanoma create unique tumor neoantigens. These neoantigens are recognized and killed by CD8+ T cells, offering a new therapeutic target for various cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Mutations in splicing factors can generate tumor-specific neoantigens.
- SF3B1 is a key splicing factor frequently mutated in uveal melanoma.
Purpose of the Study:
- To investigate if SF3B1 mutations in uveal melanoma generate immunogenic neoantigens.
- To determine if these neoantigens are recognized by T cells and can be therapeutic targets.
Main Methods:
- Analysis of SF3B1 mutations in uveal melanoma.
- Identification and characterization of neoepitope-specific CD8+ T cells.
- Single-cell analyses of T cell receptor repertoires.
- In vitro assays to assess T cell recognition and killing of tumor cells.
Main Results:
- SF3B1 mutations in uveal melanoma generate shared, tumor-specific neoantigens.
- A subset of patients (20%) with SF3B1-mutated tumors harbor memory CD8+ T cells specific for these neoantigens.
- Expanded CD8+ T cell clones recognize and kill SF3B1-mutated tumor cells.
- Some T cell receptors from blood were also found in tumors.
Conclusions:
- SF3B1-mutated uveal melanomas present immunogenic neoantigens recognized by CD8+ T cells.
- These neoantigens represent a promising new class of therapeutic targets for uveal melanoma and potentially other cancers driven by splicing factor mutations.
