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)

1 U932 - Immunité et cancer
2 Institut Curie [Paris]
3 CIC1428 IGR-CURIE
4 U830 - Unité de génétique et biologie des cancers
5 Département de Recherche Translationnelle
6 PSL - Université Paris sciences et lettres
7 Laboratoire de Spectrométrie de Masse Protéomique

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

Domaines: Sciences du Vivant [q-bio]

Jeremy Bigot, Ana Lalanne, Francesca Lucibello, Paul Gueguen, Alexandre Houy, et al.. Splicing Patterns in SF3B1 -Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes. Cancer Discovery, 2021, 11 (8), pp.1938-1951. ⟨10.1158/2159-8290.CD-20-0555⟩. ⟨hal-03877504⟩