Glioblastoma Hijacks Immune Cells: Macrophages Found to Feed Cancer Cells by Consuming Myelin

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Glioblastoma Hijacks Immune Cells: Macrophages Found to Feed Cancer Cells by Consuming Myelin

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Glioblastoma Hijacks Immune Cells: Macrophages Found to Feed Cancer Cells by Consuming Myelin

New Research Unveils Macrophages’ Role in Fueling Glioblastoma Growth by Consuming Myelin and Producing Lipids.

In a groundbreaking discovery, scientists have found that macrophages, immune cells traditionally known for protecting the body, can actually aid in the progression of brain cancer by consuming nerve myelin and producing lipids that nourish cancer cells.

A research team led by Leila Akkari from the Netherlands Cancer Institute has published their findings in the prestigious journal *Cell*. They discovered that in glioblastoma, a highly aggressive form of brain cancer, macrophages can consume myelin—a fatty substance that insulates nerve fibers. This process transforms the macrophages into lipid-laden cells, which then release these lipids to feed cancer cells that cannot directly utilize myelin, thus meeting the cancer cells’ metabolic demands and promoting tumor growth.

Akkari, an expert in tumor-associated macrophages, especially in liver and brain cancers, targeted macrophages in glioblastoma due to the tumor’s notorious aggressiveness and the high heterogeneity of both cancer and immune cells within it. Despite being crucial to understanding the disease, the molecular basis of macrophage diversity and function in glioblastoma has remained largely unknown, driving Akkari’s interest in this area.

In their study, Akkari’s team created two mouse models of glioblastoma that mimicked the key features of human glioblastoma, both in tumor development and response to treatment. In one model, they observed that primary glioblastoma cancer cells predominantly resembled oligodendrocyte precursor cells (OPCs), while during recurrence, these cells shifted to a mesenchymal-like (MES) state, similar to what is seen in human glioblastomas.

Further analysis revealed that macrophages expressing GPNMB, which share transcriptional characteristics with lipid-laden macrophages (LLMs), significantly increased in recurrent tumors with mesenchymal-like cancer cells. Previously, LLMs had been identified in studies on obesity, atherosclerosis, and neurodegenerative diseases, but their presence in brain tumors was unprecedented. Subsequent analysis confirmed that GPNMB-expressing macrophages were indeed lipid-laden macrophages.

The study also found a strong correlation between lipid-laden macrophages and mesenchymal-like glioblastoma cells, along with a negative correlation with lymphocyte infiltration in patient samples, indicating that these macrophages play a detrimental role in the tumor environment.

Using various techniques, Akkari’s team further confirmed that lipid-laden macrophages co-localize with mesenchymal-like glioblastoma cells, suggesting a close and possibly cooperative relationship. The researchers then investigated the origins of these lipid-laden macrophages. Their findings indicated significant changes in chromatin accessibility, with downregulation of genes related to immune response and upregulation of lipid absorption pathways, such as the lipid receptor CD36. Lipidomic analysis showed that these macrophages accumulated cholesterol, sphingolipids, and triglycerides, not through de novo synthesis but by scavenging from the tumor microenvironment.

This discovery prompted comparisons to foam cells observed in neurodegenerative diseases, which consume cholesterol-rich myelin fragments. The researchers confirmed that lipid-laden macrophages in glioblastoma also consume myelin, transforming into their lipid-laden state and releasing cholesterol into the tumor stroma, further fueling tumor growth.

Moreover, when co-cultured with cancer cells, macrophages that had depleted their myelin reserves could inhibit cancer cell proliferation. However, introducing macrophages restored the cancer cells’ growth capacity, indicating that lipid-laden macrophages not only detoxify cancer cells but also promote their proliferation by providing necessary lipids.

Interestingly, Akkari’s team discovered that lipid-laden macrophages not only support cancer cell growth by releasing lipids but also by directly transferring lipid-packed vesicles to the cancer cells. This finding highlights the significant role these macrophages play in nurturing tumor cells.

The good news is that targeting these macrophages offers potential therapeutic strategies. The researchers tested inhibitors against lipid receptors such as CD36 and molecules involved in lipid efflux like ABCA1 or LXR, finding that these could enhance the effectiveness of radiotherapy or directly kill cancer cells.

Finally, by examining tumor patient databases, the team found that the levels of lipid-laden macrophages could predict glioblastoma patients’ survival rates and their response to immunotherapy.

In summary, this study reveals a novel mechanism by which glioblastoma co-opts macrophages to fuel its growth, providing potential biomarkers for clinical diagnosis and new targets for glioblastoma treatment.

Glioblastoma Hijacks Immune Cells: Macrophages Found to Feed Cancer Cells by Consuming Myelin

References:

[1].Kloosterman et al., Macrophage-mediated myelin recycling fuels brain cancer malignancy, Cell. 2024. doi:10.1016/j.cell.2024.07.030

[2].https://www.nki.nl/research/research-groups/leila-akkari/

(source:internet, reference only)

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