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

• Published in: Cancer discovery Vol. 11; no. 8; pp. 1938 - 1951
• Main Authors: Bigot, Jeremy, Lalanne, Ana I, Lucibello, Francesca, Gueguen, Paul, Houy, Alexandre, Dayot, Stephane, Ganier, Olivier, Gilet, Jules, Tosello, Jimena, Nemati, Fariba, Pierron, Gaelle, Waterfall, Joshua J, Barnhill, Raymond, Gardrat, Sophie, Piperno-Neumann, Sophie, Popova, Tatiana, Masson, Vanessa, Loew, Damarys, Mariani, Pascale, Cassoux, Nathalie, Amigorena, Sebastian, Rodrigues, Manuel, Alsafadi, Samar, Stern, Marc-Henri, Lantz, Olivier
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.08.2021
• Subjects: Alternative Splicing; Humans; Life Sciences; Melanoma - genetics; Phosphoproteins - genetics; RNA Splicing Factors - genetics; Uveal Neoplasms - genetics
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-20-0555

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 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 -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 -mutated tumor cells, supporting the use of this new family of neoantigens as therapeutic targets. SIGNIFICANCE: Mutations of the splicing factor 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. .