A study led by the Biomedical Research in Melanoma Group at the Vall d’Hebron Research Institute (VHIR) has identified the p38α protein as a potential therapeutic target for improving melanoma response to immunotherapy. The study, published in Nature Communications, was conducted in collaboration with the Dermatology and Pathology Departments of Vall d’Hebron University Hospital, the Childhood Cancer and Blood Disorders group at VHIR, the Vall d’Hebron Institute of Oncology (VHIO), the Multiple Sclerosis Centre of Catalonia (Cemcat), the National Centre for Genomic Analysis (CNAG) and the Barcelona Biomedical Research Park (PRBB).

Immunotherapy has transformed the treatment of melanoma in recent years, but not all patients respond to these treatments, and some tumours develop resistance. “Identifying the mechanisms that enable melanoma to evade the action of the immune system and develop resistance to immunotherapy is one of the key research areas for advancing towards more effective treatments”, says Dr. Paula Granado Martínez, who carried out her doctoral thesis in the Biomedical Research in Melanoma group at VHIR.

p38α contributes to resistance to immunotherapy

In this study, the VHIR team investigated the role of the p38α protein in melanoma progression and the tumour immune microenvironment. This protein has a dual role in melanoma: it helps protect cells against ultraviolet light, preventing them from becoming malignant, but once melanoma is established, it supports tumour growth and creates conditions that restrict the anti-tumour immune response.

Experiments in animal models* of melanoma, human samples and cell cultures showed that, when p38α is removed from melanoma cells, the tumour becomes more sensitive to the action of the immune system. Specifically, increased activity was observed in cells such as CD8+ T lymphocytes and natural killer cells, as well as in other signals associated with the inflammatory response.

These changes also have an important effect on the response to immunotherapy. The team found that p38α contributes to resistance to anti-PD-1 treatment, one of the most widely used immunotherapies for melanoma. By contrast, melanomas lacking p38α are more sensitive to the treatment.

The researchers therefore investigated whether blocking this protein with clinically validated inhibitors could enhance the effect of immunotherapy. The results showed that the inhibitors, when administered on their own, did not reduce tumour size. However, combining the inhibitors with immunotherapy significantly improved tumour control and, in some of the animals studied, even achieved complete tumour elimination.

“This study identifies p38α as a new potential target for addressing resistance to immunotherapy. Combining p38α inhibitors with anti-PD-1 could be a strategy for making tumours more sensitive to treatment,” says Dr. Juan Ángel Recio, head of the Biomedical Research in Melanoma Group at VHIR.

Further studies will be needed to validate the findings in human samples and subsequently in clinical trials involving patients, in order to assess the safety and efficacy of this therapeutic combination.

A set of nine genes to predict response to immunotherapy

In addition to the role of p38α in tumour growth and the immune response, the study identified a signature comprising nine genes associated with this protein. By analysing the expression of these genes, the researchers found that this signature can distinguish tumours that are more likely to respond to immunotherapy from those that are less likely to do so. This profile is also associated with improved survival.

“This finding points to a possible future use of this signature as a tool for identifying patients who are more likely to benefit from immunotherapy”, concludes Dr. Recio.

*Institutional Statement on the Use of Research Animals