The treatment of metastatic melanoma has advanced significantly in recent years thanks to immunotherapies and targeted therapies. Some patients are now being cured of their disease, while others do not respond to treatment and their prognosis remains poor. Actively pursuing research in this field is a major priority for Prof. Caroline Robert, head of the onco-dermatology department at Gustave Roussy, and her team. Here’s a closer look at the advances made and the challenges ahead.  

With more than 16,000 new cases per year in France, melanoma remains the most aggressive form of skin cancer. Nevertheless, thanks to research and the progress made, 70% of patients respond to targeted therapies, and 20% of metastases disappear completely. However, it is not uncommon to see a relapse after a few months or years. Immunotherapies, when effective—in 20 to 55% of patients—can, in some cases, lead to lasting complete remission, even after treatment is stopped.  

In recent years, efforts have focused on finding new treatments and identifying markers that predict response or resistance.

The Role of Persistent Cells

Professor Caroline Robert’s team was able to identify and characterize persistent cancer cells—cells that are invisible to clinical examination and imaging yet remain present in the body after treatment. These cells may be responsible for relapses occurring several months or years after the end of treatment. The oncodermatologist and her team thus demonstrated that these persistent cells reprogram their protein production by translating a small number of messenger RNAs, which allows them to survive and trigger subsequent resistance. Furthermore, the energy consumption of these cells differs from that of other tumor cells, and this distinct metabolism may offer a therapeutic avenue.

For the first time, persistent cells were visualized in patient biopsies before and after treatment with targeted therapy or immunotherapy. This work was the subject of Dr. Sara Faouzi’s dissertation and was presented at an international conference in June 2022. Prof. Robert’s team also demonstrated that these persistent cells could be eliminated using an inhibitor of an enzyme involved in the production of proteins from messenger RNA. The results, which have shown promise in cell cultures and animal models, will be used to develop new, effective drugs to combat tumor progression.

To understand why persistent cells are not destroyed by the immune system, the laboratory has developed tests to evaluate the influence of these cells on immune cells: lymphocytes and monocytes. These tests show that a protein produced by persistent cells appears capable of paralyzing the immune system. The team is currently working to better characterize this protein and find a way to counteract its action.

New Biomarkers Predicting Response to Immunotherapies

Another of its advances is the ability to predict which individuals are likely to respond—or not—to immunotherapy treatment, thanks to the discovery of a new biomarker. It is based on the detection of an interaction between the PD-1 and PD-L1 receptors, which are directly targeted by immunotherapies. Professor Caroline Robert’s team is currently evaluating this biomarker in patients with lung cancer.

The researchers have also been studying the LDH marker, an enzyme found in the blood; its various forms, characterized in both the blood and metastases, provide a better understanding of its significance. These findings, which are currently being confirmed, will be particularly useful for better identifying patient profiles.