From predisposing genetic variants to public (shared) tumor-specific neo-antigens in uveal melanoma

The project "From predisposing genetic variants to public (shared) tumor-specific neo-antigens in uveal melanoma" is supported by the Assistant Secretary of Defense for Health Affairs endorsed by the U.S. Department of Defense in the context of the Rare Melanomas Focused Program Award, under Award No. HT9425-23-1-0722. The project receives a grant of 1.9M$ for 4 years, starting on september 2023.  It is coordinated by Dr. Marc-Henri STERN, team leader of the DNA Repair and Uveal Melanoma (D.R.U.M) team within the U830 unit at the Institut Curie Research Center. It comprises 3 sub-projects led by Dr. Marc-Henri Stern, Dr. Manuel Rodrigues and Dr. Olivier Lantz. The consortium also includes the Melanoma Patients Network Europe (MPNE), represented by Dr. Bettina Ryll and Jo Gumbs

Melanomas do not only affect the skin. They also appear in the inner part of the eye, and this type of tumor is called uveal melanoma. Each year, around 750 new patients are diagnosed with uveal melanoma in France, and 3,500 patients in the U.S.A. Uveal melanomacan most often be treated effectively when localized in the eye, but one third to one half of the patients will eventually develop metastases, mostly in the liver. Patients suffering from uveal melanoma metastases face limited treatment options and have a dismal prognosis.

The research program will bring answers to crucial questions such as: Why uveal melanoma affects some and not others? How uveal melanoma develops? How the immune system recognizes uveal melanoma or not? As part of the project, unique new tools will be developed to study uveal melanoma and to find new treatments, which will have a tremendous impact both on the scientific community and on patients and relatives.

Our research program addresses three crucial topics:

 

Genetic predisposition to uveal melanoma

Uveal Melanoma is more common in individuals of European ancestry. This increased incidence is not related to sun exposure or lifestyle. In addition, some families show an unexpected high occurrence of uveal melanoma. These observations suggest that genetic variants, transmitted (inherited) from parents to children, can convey a higher risk to develop uveal melanoma.

By studying large numbers of patient samples, research will establish a comprehensive list of clinically relevant genetic risk factors. This will provide a better understanding of the disease: why are individuals of European ancestry 10 times more at risk? Why do some patients develop aggressive uveal melanoma with a high risk of metastases, while others have a more favorable outcome? The mutated genes that are discovered will be analyzed in all uveal melanoma patients and their relatives in the future. A new type of test, from a simple blood sample that will allow physicians to estimate the risk for a patient to develop metastasis and adapt the follow-up accordingly.

 

Oncogenic transformation of healthy melanocytes into melanoma

Normal melanocytes from the eye can transform into uveal melanoma with either a high-risk or a low-risk of metastatic relapse. The recent results from the teams involved in the project strongly suggest that this transformation into high- or low-risk uveal melanoma largely depends on inherited features. Understanding how normal melanocytes from the eye transform into uveal melanoma is a key aspect of understanding the disease itself.

Normal melanocytes will be isolate from enucleated patients and transform them by introducing the specific genetic alterations seen in high- or low-risk uveal melanoma. They will then be compared with the uveal melanoma cells coming from the same patients and assess their biological characteristics and aggressiveness. Understanding these first steps in the formation of uveal melanoma will provide the knowledge necessary for the development of innovative therapeutic strategies. The transformed melanocytes that will be obtain represent valuable research tools that will be shared with the scientific community.

 

Immune response towards uveal melanoma cells

Mutations in cancer cells can create abnormal proteins, called tumor-specific neo-antigens, that can be recognized by the patient’s immune cells. These neo-antigens are powerful targets for therapeutic vaccines and other immunotherapies that aim to generate or amplify the patient’s immune response against the tumor. Uveal melanoma is characterized by an extremely low mutation rate. Despite this paucity of classic sources of tumor neoantigens, teams have demonstrated the presence of an immune response in metastatic uveal melanoma patients. However, the recognized neoantigens in these cases are not yet identified.

By using patient tumor samples and immune cells from the blood, uveal melanoma cell lines and patient derived xenograft tumors in mice, novel uveal melanoma-specific neoantigens that are shared between patients, and common or specific for the different uveal melanoma subtypes, will be discover. The systemic (blood) immune response towards these neo-antigens at different stages of the disease will also be analyse, in order to demonstrate their clinical relevance. These neo-antigens will lay the ground for therapeutic vaccines and other immunotherapies for all subtypes of uveal melanoma.

The research program will answer key questions that will directly benefit patients. Through the patient organization MPNErare, uveal melanoma patients will be involved and informed throughout the project and will gain a better understanding about how uveal melanoma emerges, whether they need to be concerned or not for their relatives, how their immune system can be boosted to recognize and fight the tumor and, in general, how fundamental and translational research contribute to a better patient care.

Contact :
Principal Investigator : Dr. Marc-Henri Stern
Project leader : Dr. Manuel Rodrigues
Project leader: Dr. Olivier Lantz
Program manager: Dr. Leanne de Koning
Melanoma Patients Network Europe