Do microglia hold the key to managing melanoma brain metastases?
Researchers have identified a key role microglia play in the progression of melanoma brain metastases.
A research team led by Berta Sanchez-Laorden at the Institute for Neurosciences (Alicante, Spain) has identified that a transcriptomic shift and subsequent activation of a key signaling pathway occurs in microglia during melanoma brain metastases (MBM) progression. Targeting this pathway could promote antitumor immunity and improve responses to immunotherapies.
Melanoma, the most aggressive form of skin cancer, displays a natural tendency to metastasize to the brain. In recent years improvements have been made in the therapeutic management of patients with MBM, particularly with combination treatments based on immune checkpoint inhibition (ICI).
Despite this, a proportion of patients still do not benefit from ICI. It is thought that the unique characteristics of MBM create a challenge for its effective management and response to immunotherapies, such as ICI. However, the biology of MBM is still poorly understood.
Previous studies have demonstrated a pro-tumoral role of macrophages in breast cancer brain metastases, highlighting that they may also be involved in metastases of other cancers, such as MBM. Therefore, improving our understanding of the immune microenvironment in MBM could help to improve the management of these patients.
Recreating the tumor microenvironment with 3D bioprinting technology
Cancer models retaining the original tumor characteristics allow for rapid evaluation of drug responses.
In this study, the researchers used mouse models of brain metastases, pharmacological targeting and single-cell transcriptomic analysis to analyze the role of microglia, often referred to as the brain’s macrophages, in MBM progression and response to immunotherapy.
The results indicated that in the early stages of brain colonization, microglia have a protective role in which they kill and phagocytize tumor cells. However, as MBM progresses, microglia undergo a transcriptomic shift, which involves the expression of genes associated with pro-tumoral polarization in macrophages.
The researchers also demonstrated that blocking the pathway enabled microglial cells to send signals to other immune cells, such as natural killer cells and cytotoxic T-cells, which effectively attacked tumor cells and enhanced the response to immunotherapy.
“Immune checkpoint inhibitors have revolutionized melanoma treatment, but not all patients respond well to these therapies. Our study suggests that combining them with Rela/NF-kB inhibitors could improve their effectiveness in treating brain metastases,” commented Sánchez-Laorden.
This study highlights that targeting microglia could be used in combination with existing immunotherapies to improve the therapeutic management of patients with MBM and potentially metastases of other cancers. The researchers plan to continue their work by exploring how this knowledge can be translated into clinical treatments.
