Brain metastases are one of the most severe complications of melanoma, the most aggressive type of skin cancer. Researchers at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) in Elche, have identified a strategy to slow their progression, which could improve the response to current treatments. The study, published today in Cancer Cell, demonstrates that microglia, a type of resident immune cell in the brain, can be manipulated to reduce brain metastases growth and enhance immunotherapy responses in preclinical mouse models.

Researchers from the lab led by Berta Sánchez-Laorden, part of the Cell Plasticity in Development and Disease group at IN, discovered that microglia can be reprogrammed from a tumor-promoting state to one that strengthens antitumor responses. “We have identified a key signaling pathway, Rela/NF-kB, that, when blocked, reverses the protumoral function of microglia and activates an immune response against tumors”, explains Sánchez-Laorden, the study’s lead researcher.

Using mouse models of brain metastases and advanced sequencing techniques, the researchers analyzed the role of microglia in this context. F. Javier Rodríguez Baena, the first author of the article, explains: “We demonstrated that when we block Rela/NF-kB signaling in microglia, these cells begin to send signals to other immune cells, such as cytotoxic T lymphocytes and natural killer (NK) cells, which effectively attack tumor cells”.

The researchers also analyzed patient samples, confirming that this strategy could have future clinical applications. Additionally, the team observed that blocking this signaling pathway also enhances the response to immunotherapy in preclinical mouse models. “Immune checkpoint inhibitors have revolutionized melanoma treatment, but not all patients respond well to these therapies”, notes Sánchez-Laorden, adding, “Our study suggests that combining them with Rela/NF-kB inhibitors could improve their effectiveness in treating brain metastases”.

Therapeutic Implications and Future Research

The study’s findings indicate that manipulating microglia could be used in combination with existing immunotherapies to boost their effectiveness in patients with brain metastases. “These results allow us to explore new therapeutic combinations that could significantly improve patient survival”, highlights Sánchez-Laorden.

This research represents a significant breakthrough in understanding the interactions between the brain’s immune system and metastases in this organ, opening new avenues to improve the prognosis of patients with advanced cancer. These findings could lead to innovative therapeutic strategies for melanoma patients and other cancers that metastasize to the brain, such as breast or lung cancer. “This is just the beginning. Our next goal is to further explore how this knowledge can be translated into clinical treatments and evaluate the potential of Rela/NF-kB inhibitors already approved for other indications”, says Rodríguez-Baena.
The team collaborated with the Cellular Plasticity and Neuropathology lab at IN, led by researcher José López-Atalaya, an expert in microglia and sequencing data analysis, as well as with the team of Professor Gema Moreno Bueno from the Sols-Morreale Biomedical Research Institute (IIBM-CSIC-UAM) and the MD Anderson Foundation (both in Madrid), who provided patient samples.

This research was made possible thanks to funding from the Melanoma Research Alliance, the FERO Foundation, the Spanish State Research Agency - Ministry of Science, Innovation, and Universities, and the Carlos III Health Institute (ISCIII), among others.
More information: https://youtu.be/gvXpG5kY5ng