A study by the melanoma group at the National Center for Oncological Research (CNIO) has discovered a mechanism by which melanomas and other aggressive tumors prevent the immune system from recognizing and attacking them.
The study, led by Marisol Soangas, also helps understand why when melanoma spreads to other organs, giving rise to metastases, it often develops resistance to conventional immunotherapy.
The work is published in «Nature Cancer,» with Xavier Catena, currently at Lund University (Sweden), as the first author. After conducting studies on cells, mice, and over 150 patient databases, the team found that melanoma cells secrete a protein called midkine, which reduces the number of specialized cells in tumor recognition, dendritic cells.
Additionally, midkine reprograms dendritic cells to change their function to favor tumor development. «In this article, we discovered that Midkine acts as both a shield and an accelerator at the same time: it avoids the recognition and elimination of tumor cells and actively facilitates the progression and spread of malignant cells,» explains Soangas.
Dendritic cells typically act as vigilant defenders, identifying foreign molecules in pathogens like viruses and bacteria, as well as in tumors. They then present this information to other defensive cells, cytotoxic T lymphocytes, to eliminate malignant cells. This article now shows that in melanomas, Midkine reduces the number of dendritic cells and alters their functioning.
«The most relevant aspect is that I understood how, through Midkine, melanoma not only stops or leaves the immune system cold, but perverts it in its favor, actively contributing to dissemination,»
Once the mechanism by which midkine blocks the immune system was discovered, research shifted to analyzing its impact on treatments. Therefore, the CNIO group demonstrates in animal models that when the action of Midkine is prevented, the effectiveness of vaccines targeting dendritic cells is improved.
Furthermore, preventing the action of Midkine also enhances the therapeutic action of one of the most common forms of immunotherapy, immune checkpoint inhibitors.
CNIO researchers also analyzed data from large patient cohorts and found a genetic company associated with midkine in dendritic cells that correlates with a poorer prognosis. This finding extends beyond melanoma, as similar effects have been observed in lung, breast, endometrial, adrenal gland, and mesothelioma cancers, among others.
«Our results suggest that inhibiting the midkine protein could reactivate dendritic cells and improve therapies against different types of aggressive tumors,» adds Soangas.
These results add new information to previous studies by the CNIO Melanoma group, which have already demonstrated that the midkine protein can promote melanoma metastasis and alter the function of other components of the immune system.
