On the occasion of May 24, the European day dedicated to the prevention of melanoma, we interviewed Vincenzo Russo, Associate Professor in General Pathology at Vita-Salute San Raffaele University and Group Leader of the Immuno-biotherapy of melanoma and solid tumors lab at San Raffaele Hospital, to focus on the pathogenesis and treatment of this tumor.

What is melanoma?

Melanoma is a malignant tumor that constitutes approximately 25% of skin tumors. Unlike tumors of epithelial cells, which constitute the remaining 75% of skin tumors, melanomas are very aggressive and require early diagnosis to be treated. This tumor forms when the DNA of melanocytes is damaged, usually by the prolonged and inappropriate exposure to UVB sun rays. When DNA damage occurs at the level of oncogenes, and is no longer repaired by cell intrinsic mechanisms, melanocytes can become neoplastic and start to proliferate uncontrollably.

“In Italy, in recent years, there has been a 30% increase of melanomas, reaching approximately 13 thousand new cases in 2024” says Professor Russo, who adds: “these numbers are linked to the inappropriate and excessive use of sunbeds, as well as exposure to the sun without the use of adequate protection.”

Treating melanoma: molecular targeted therapy and immunotherapy

Today we know most of the genetic alterations that contribute to melanoma formation. For example, we are aware of the role of some oncogenes, such as BRAF, whose mutation has been very well studied.

The most common mutation of BRAF (V600E) results in the replacement of the valine amino acid in position 600 with glutamic acid within the active site of the encoded protein. Such mutation results in the constitutive activation of BRAF, which, in turn, eventually leads to uncontrolled cell proliferation.

“The studies conducted for more than 10 years on this peculiar mutation allowed the development of highly specific drugs (so-called, molecular targeted drugs) that block the active site of the mutated BRAF protein, thus inhibiting its constitutive activation. This targeted therapy can be very effective in promoting and maintaining tumor remission” explains Russo.

BRAF mutation is present in 50% of patients suffering from melanoma, but currently there are additional oncogene mutations under investigation, such as the one involving the NRAS gene. “At San Raffaele we are currently conducting a study with a molecular target against the NRAS mutation, which affects 20 percent of patients with melanoma”, says the Professor.

Historically, genetic and immunological studies of melanoma have been instrumental for the development and advancement of cancer immunotherapy - that is, the set of strategies that aim at restoring and/or enhancing the anti-tumor immune action.

In this context, in 2011 the US Food and Drug Administration approved the first class of immune checkpoint inhibitors to treat metastatic melanoma. “This event marked a major milestone in the history of Oncology. Since then, immunotherapy has become increasingly important in the treatment of tumors”, comments Professor Russo.

Immune checkpoints are molecules, such as CTLA-4, PD-1 and LAG3, expressed on the surface of T lymphocytes. When these molecules bind to a counter-receptor expressed by another body cell, the immune action of T lymphocytes becomes de-activated. This system of “breaks” on the activity of T cells is crucial to avoid unwanted immune reaction against body’s own, healthy cells.

However, when it comes to cancer, such breaks need to be released, so that T lymphocytes can kill tumor cells. Immune checkpoint inhibitors are a class of drugs that hide immune checkpoints from their counter-receptors, eventually unlocking the immune action of T cells, which thus can kill cancer cells. 

Cancer immunotherapy, particularly immune checkpoint inhibitors, works for approximately 50-60% of patients with melanoma, but at the same time research is still investigating the mechanisms that make these drugs ineffective in the remaining 40-50% of patients.

“Today, more than half of patients with melanoma, if adequately treated, survive for more than ten years. This is an important result, because before 2011, less than 10% of subjects managed to survive for this time,” adds Russo, who specifies: “however, we still lack a series of molecular, cellular and immunological information on the processes that prevent 40-50% of patients with melanoma from responding positively to treatment”.

Russo’s Lab research lines

The Laboratory of Immuno-biotherapy of melanoma and solid tumors of Prof. Russo focuses on the immunology and immunotherapy of tumors and has always used melanoma as a study model.

 “Why this tumor? Because it was the first one for which relationships with the immune system were recognized” specifies Russo, who adds: “over the years we have discovered that tumor cells, including melanoma, produce oxysterols, molecules of oxidized cholesterol that inhibit the body’s immune response”.

In this context, LXR receptors (Liver X Receptors) play a crucial role: they are proteins that, by binding specifically to oxysterols, regulate various cellular functions, including cholesterol metabolism. “One type of these receptors, the alpha LXRs, act as a bridge between the production of cholesterol, oxysterols and the immune system, and this connection damages the immune response” adds the Professor, who clarifies: “in collaboration with a team of chemists from the University of Perugia, we are trying to use LXR antagonists to block the action of these receptors and thus restore the functionality of the immune system”.

Additional immunotherapy strategies and future perspectives

Currently, other immunotherapy strategies are being developed such as those based on mRNA vaccines. For example, an ongoing clinical trial conducted in various countries, including Italy, is testing a therapeutic mRNA vaccine against melanoma. This vaccine has been developed upon the identification of specific cancer-antigens isolated from metastases that had been surgically resected from patients with melanoma. Researchers are testing the use of this mRNA vaccine in combination with immune checkpoint inhibitors, such as anti-PD-1 drugs.

“This clinical trial is testing the use of this mRNA vaccine + anti-PD-1, and the first results are interesting. Such combination seems to be more effective than single immunotherapy with immune checkpoints, but conclusive data will be needed to understand if we have an additional option to treat melanoma” adds Professor Russo.

Another immunotherapeutic option is represented by isolated and expanded Tumor Infiltrating  Lymphocytes (TILs).  “TILs are T lymphocytes that are isolated from the tumor, expanded in vitro and re-administered to the patient. TILs constitute an FDA-approved therapy for patients with metastatic melanomas that are unresponsive or resistant to immunotherapy with anti-PD-1 antibodies” adds Professor Russo, who concludes: “Research in the immunotherapy of melanoma is intense and increasingly developing. I think that we’re going towards a future in which melanoma could become a chronic disease that we’ll be increasingly able to keep under control”.