Splicing Patterns in SF3B1 -Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes
Jeremy Bigot
(1)
,
Ana Lalanne
(2, 3)
,
Francesca Lucibello
(1)
,
Paul Gueguen
(1)
,
Alexandre Houy
(4)
,
Stephane Dayot
(4)
,
Olivier Ganier
(4)
,
Jules Gilet
(1)
,
Jimena Tosello
(1)
,
Fariba Nemati
(5, 3)
,
Gaelle Pierron
(2)
,
Joshua Waterfall
(4)
,
Raymond Barnhill
(5, 6)
,
Sophie Gardrat
(4, 2)
,
Sophie Piperno-Neumann
(5, 4)
,
Tatiana Popova
(4)
,
Vanessa Masson
(7)
,
Damarys Loew
(7)
,
Pascale Mariani
(2)
,
Nathalie Cassoux
(2)
,
Sebastian Amigorena
(1)
,
Manuel Rodrigues
(4, 2)
,
Samar Alsafadi
(4, 5)
,
Marc-Henri Stern
(4)
,
Olivier Lantz
(3, 1)
Paul Gueguen
- Fonction : Auteur
- PersonId : 770558
- ORCID : 0000-0003-2930-6073
- IdRef : 261885200
Alexandre Houy
- Fonction : Auteur
- PersonId : 1196355
- ORCID : 0000-0001-6267-2353
Gaelle Pierron
- Fonction : Auteur
- PersonId : 1196357
- ORCID : 0000-0002-2536-7680
Joshua Waterfall
- Fonction : Auteur
- PersonId : 797639
- ORCID : 0000-0002-3762-5050
- IdRef : 227577132
Raymond Barnhill
- Fonction : Auteur
- PersonId : 1196358
- ORCID : 0000-0001-8086-8544
Sophie Piperno-Neumann
- Fonction : Auteur
- PersonId : 792417
- ORCID : 0000-0001-9915-2810
Damarys Loew
- Fonction : Auteur
- PersonId : 762943
- ORCID : 0000-0002-9111-8842
Manuel Rodrigues
- Fonction : Auteur
- PersonId : 769887
- ORCID : 0000-0002-5443-0802
Samar Alsafadi
- Fonction : Auteur
- PersonId : 1196359
- ORCID : 0000-0002-0060-1346
Marc-Henri Stern
- Fonction : Auteur
- PersonId : 807138
- ORCID : 0000-0002-8100-2272
- IdRef : 074099191
Olivier Lantz
- Fonction : Auteur
- PersonId : 756941
- ORCID : 0000-0003-3161-7719
- IdRef : 092426565
Résumé
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