Lipid-Laden Macrophages Recycle Myelin to Feed Glioblastoma

Abstract

Tumor-associated microglia and macrophages (TAM) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment. Given the heterogeneity and plasticity of TAMs in the GBM tumor microenvironment, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman and colleagues identified a subpopulation of glycoprotein nonmetastatic melanoma protein Bhigh lipid-laden microglia and macrophages (LLM) in GBM. Mesenchymal-like GBM cells help generate the LLM phenotype. Reciprocally, LLMs are epigenetically rewired to recycle myelin and transfer the lipid from myelin to cancer cells, fueling mesenchymal-like GBM progression in a liver X receptor/ABCA1-dependent manner. Together, leveraging LLMs opens new therapeutic possibilities for rewiring the metabolism-mediated tumor-TAM interaction during GBM progression.

Figure 1.

LLM is a GPNMB^high TAM subpopulation that is enriched with lipid droplets. LLMs display immunosuppressive characteristics and promote the proliferation of GBM cells, particularly MES-like GBM cells. Myelin from the GBM TME induces a lipid-laden phenotype in macrophages by activating liver X receptor (LXR) and upregulating H3K27me3. Kloosterman and colleagues demonstrated a metabolic interplay pattern between LLMs and MES-like GBM cells (8). TAM phagocytoses myelin debris through the lipid receptor CD36, leading to a shift of TAMs from an inflammatory to an immunosuppressive phenotype. Cholesterol-rich myelin debris triggers the liver X receptor and upregulates the downstream lipid exporters ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1). LLMs process myelin into cholesterol ester, which can be utilized by MES-like GBM cells. Cholesterol ester–derived fatty acids are then incorporated into phospholipids to construct cell membranes during cancer cell proliferation. Additionally, the phagocytosis in LLMs also helps to bypass the myelin lipotoxic effect in cancer cells. The interaction between LLMs and MES-like GBM cells reveals a new cell–cell communication pattern in the coevolving GBM ecosystem. OPC, oligodendrocyte progenitor. (Created with BioRender.com.)