Splicing Patterns in SF3B1-Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes.

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.

• Authors: Jeremy Bigot, Ana I Lalanne, Francesca Lucibello, Paul Gueguen, Alexandre Houy, Stephane Dayot, Olivier Ganier, Jules Gilet, Jimena Tosello, Fariba Nemati, Gaelle Pierron, Joshua J Waterfall, Raymond Barnhill, Sophie Gardrat, Sophie Piperno-Neumann, Tatiana Popova, Vanessa Masson, Damarys Loew, Pascale Mariani, Nathalie Cassoux, Sebastian Amigorena, Manuel Rodrigues, Samar Alsafadi, Marc-Henri Stern, Olivier Lantz
• Journal: Cancer discovery (Cancer Discov) Vol. 11 Issue 8 Pg. 1938-1951 (08 2021) ISSN: 2159-8290 [Electronic] United States
• PMID: 33811047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Phosphoproteins
• RNA Splicing Factors
• SF3B1 protein, human

Topics

• Alternative Splicing
• Humans
• Melanoma (genetics)
• Phosphoproteins (genetics)
• RNA Splicing Factors (genetics)
• Uveal Neoplasms (genetics)