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Uveal melanoma: new findings on therapeutic targets

In an article published in the journal Cancer Discovery, researchers from Institut Curie and Inserm shed light on new therapeutic targets shared between patients to combat uveal melanoma.

A cancer of the eye that affects almost 600 adults per year, uveal melanoma develops on the walls of the eye. Like the skin, our eyes contain melanocytes, cells that are responsible for producing melanin, a pigment that protects us from the sun’s rays. Uveal melanoma leads to metastases in the liver in 20 to 30% of cases. The outlook in this case is unfavorable, with a 52% survival rate at one year. The currently available, such as chemotherapy and immunotherapy, have far not been proven effective enough. Recently, Tebentafusp - a molecule able to redirect the patient’s CD3+ T-cells against an antigen of the tumor cells - produced promising results in phase-III clinical trials.

Within this context, research on new therapeutic targets that are effective against uveal melanoma is needed. The fight against uveal melanoma is part of the SIRIC program at Institut Curie.
In a recently published study, researchers from Institut Curie and Inserm evidence new therapeutic targets that are shared between patients, and specific to the tumor. These targets are abnormal cellular peptides developed by the tumor, and recognized by the T-cells, cells which can then destroy tumor cells. These results were published in the journal Cancer Discovery on April 2, 2021.


A new therapeutic target, neoepitopes due to mutations of the SF3B1 splicing factor

20 to 25% of uveal melanomas carry a genetic anomaly: a mutation of the splicing factor[1], SF3B1. This mutation leads to splicing anomalies that generate new messenger RNA sequences which themselves produce new peptides (protein components).

"The purpose of our study was to determine whether patients who have the SF3B1 mutation develop an immune response directed against these peptides", explains Olivier Lantz, head of the clinical immunology laboratory at the Institut Curie hospital and joint-last author of the study. This is in fact the case, since neoepitopes are expressed only by the tumor’s cells and cause the destruction of these cells by the CD8 T-cells, also known as killer cells.

This discovery means that it will be possible, in time, to redirect the immune system against these specific neoepitopes

Explains Marc-Henri Stern, head of the DRUM team (DNA Repair and Uveal Melanoma) at Institut Curie. Researchers hope to soon be able to develop a vaccine that will inject a treatment to target these neoepitopes, which are both shared between patients, and specific to the tumor.

[1] Splicing is a process by which RNA transcribed from genome DNA undergo stages of cutting/connecting that lead to the elimination of certain areas in the final RNA.

Référence :
Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes

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

DOI: 10.1158/2159-8290.CD-20-0555, Cancer Discovery, 2 avril 2021