A study led by the Melanoma Biomedical Research group at the Vall d’Hebron Research Institute (VHIR) has identified the p38 protein as a potential therapeutic target to improve melanoma's response to immunotherapy. The work, published in the journal Nature Communications, was conducted in collaboration with the Dermatology and Pathological Anatomy Services of the Vall d’Hebron University Hospital, the Pediatric Cancer and Hematological Diseases group at VHIR, the Vall d’Hebron Institute of Oncology (VHIO), the Centre d’Esclerosi Múltiple de Catalunya (Cemcat), the National Centre for Genomic Analysis (CNAG), and the Barcelona Biomedical Research Park (PRBB).
Immunotherapy has transformed melanoma treatment, but not all patients respond, and some tumors develop resistance. "Identifying the mechanisms that allow melanoma to escape the immune system's action and develop resistance to immunotherapy is one of the key research lines to advance towards more effective treatments," states Dr. Paula Granado Martínez, a researcher at the Melanoma Biomedical Research group at VHIR.
The p38 protein plays a dual role in melanoma: it protects cells from ultraviolet light to prevent malignancy, but once melanoma is established, it supports tumor growth and creates conditions that restrict anti-tumor immune response. Experiments in animal models, human samples, and cell cultures have shown that eliminating p38 makes the tumor more sensitive to the immune system, increasing the activity of CD8+ T lymphocytes and natural killer cells.
These changes also significantly impact the response to immunotherapy. The team found that p38 contributes to resistance against anti-PD-1 treatment. Conversely, melanomas without p38 are more sensitive. Combining p38 inhibitors with immunotherapy notably improved tumor control and, in some studied animals, even achieved complete tumor elimination.
“"This study identifies p38 as a novel potential target for addressing immunotherapy resistance. The combination of p38 inhibitors with anti-PD-1 could be a strategy to make tumors more sensitive to treatment."
Future studies will need to validate these findings in human samples and subsequently in clinical trials to assess the safety and efficacy of this therapeutic combination.
Furthermore, the research identified a signature of nine genes associated with p38, which can distinguish tumors more likely to respond to immunotherapy from those less likely to do so. This profile is also linked to better survival.
“"This finding points to a potential future use of this signature as a tool to identify patients who are most likely to benefit from immunotherapy."
