Targeting lipid metabolism in Tumor associated macrophages as a novel approach to target tumor progression

Einleitung The physiology of the tumor microenvironment (TME) plays an important role in sketching the therapeutic response and resistance, thus justifying the recent spur to target components of the TME for cancer treatment. The various hallmarks of cancer orchestrate tumor progression, including metabolic reprograming of tumor and immune cell compartment.

Ziele Macrophages contribute crucially to the TME and are highly diverse phenotypically and functionally. The presence of tumor associated macrophages (TAMs) has been reported to correlate with all stages of tumor progression and poor prognosis. Numerous metabolites viz lipids, amino acids and iron affect the polarization of macrophages. Our study aims at investigating and deciphering the role of lipid droplet mediated fatty acid metabolism in TAMs in modulating the immune response.

Methodik Macrophages were treated with sodium oleate and lipid metabolism has been blocked by a range of small molecule inhibitors. Cells were analyzed by a wide range of methods, phenotypically (e.g. flow cytometry, fluorescence microscopy, metabolic analyses) and functionally (e.g. T cell suppression assay, adoptive cell transfer in murine tumor models).

Ergebnis Fatty acid supplementation modulates the monocyte derived macrophage differentiation process. Importantly, long chain fatty acids mediate the differentiation into immunosuppressive TAM-like macrophages. This is mediated by unsaturated fatty acids uptake, storage in lipid droplets and further metabolization of the stored fatty acids. Specific inhibition of this metabolic pathway in macrophages at any point blocks the polarization to immune suppressive macrophages and reduces tumor progression in murine tumor models.

Schlussfolgerung Considering the fatty acid enriched tumor microenvironment and the anti-inflammatory phenotype of TAMs, we propose a model in which extracellular fatty acids polarize the infiltrating monocytes into M2-like pro-tumoral macrophages. Our research aims at identifying novel drug targets for fatty acid metabolism in macrophages that can prevent immune evasion.

Publication History

Article published online:
07 September 2021