Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages

Abstract

Tumor‐associated macrophages (TAMs) promote tumor growth and metastasis by suppressing tumor immune surveillance. Herein, we provide evidence that the immunosuppressive phenotype of TAMs is controlled by long‐chain fatty acid metabolism, specifically unsaturated fatty acids, here exemplified by oleate. Consequently, en‐route enriched lipid droplets were identified as essential organelles, which represent effective targets for chemical inhibitors to block in vitro polarization of TAMs and tumor growth in vivo. In line, analysis of human tumors revealed that myeloid cells infiltrating colon cancer but not gastric cancer tissue indeed accumulate lipid droplets. Mechanistically, our data indicate that oleate‐induced polarization of myeloid cells depends on the mammalian target of the rapamycin pathway. Thus, our findings reveal an alternative therapeutic strategy by targeting the pro‐tumoral myeloid cells on a metabolic level.

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

“…However, inhibition of DGAT, an enzyme responsible for the formation of lipid droplets in myeloid cells, prevented oleate-induced immunosuppressive M2 phenotype in murine BMDMs and human monocyte-derived macrophages. Besides, mTOR inhibition in myeloid cells eliminated specific lipid droplet-dependent mitochondrial respiration in M2-like macrophages [257]. In contrast, the LD formation in TAMs from a mouse mammary adenocarcinoma model was associated with significantly inhibited tumor growth.…”

“…The importance of FAO for TAMs has been recently shown in a murine colon carcinoma model and in human colon cancer where unsaturated fatty acids (oleate) induced polarization of immunosuppressive TAMs by supporting mitochondrial respiration [257]. The up-regulation of M2 specific markers (CD206, IL-6, VEGFα, MMP9, ARG1) was observed upon oleate treatment dependent on lipid droplets (LD), that play an essential role in the catabolism of free fatty acids for mitochondrial respiration.…”

“…The up-regulation of M2 specific markers (CD206, IL-6, VEGFα, MMP9, ARG1) was observed upon oleate treatment dependent on lipid droplets (LD), that play an essential role in the catabolism of free fatty acids for mitochondrial respiration. The formation of LDs in TAMs was found in tumor tissue of patients with colon cancer [257]. However, inhibition of DGAT, an enzyme responsible for the formation of lipid droplets in myeloid cells, prevented oleate-induced immunosuppressive M2 phenotype in murine BMDMs and human monocyte-derived macrophages.…”

Biology and therapeutic targeting of tumour‐associated macrophages

“…Whereas M1-like TAMs preferentially utilize a glycolytic metabolism, M2-like TAMs employ oxidative phosphorylation and fatty acid oxidation (FAO) for energy purposes [3,[122][123][124]. Lipid metabolism in TAMs has been linked to the acquisition of an M2-like, immunosuppressive phenotype through various mechanisms [125][126][127]. For example, in both B16.F10 melanoma and MC38 colon adenocarcinoma models, Tregs promote M2-like polarization of TAMs through a mechanism involving the sterol regulatory element-binding protein 1 (SREBP1) pathway for the de novo synthesis of fatty acids [125].…”

The dynamic behavior of lipid droplets in the pre-metastatic niche

“…The novel lipid mediator CYP4A/20-HETE in TAMs promotes lung PMN formation through the M2 macrophage-derived factors transforming growth factor beta (TGF-β), stromalderived factor 1 (SDF-1), and VEGF via signal transducer and activator of transcription 3 (STAT3) signaling 83 . Wu et al provided evidence that the immunosuppressive phenotype of TAMs is controlled by LD-dependent FA metabolism that depends on the mammalian target of rapamycin (mTOR)-signaling pathway 84 . Additionally, epidermal FA-binding protein (E-FABP)-expressing TAMs produce high levels of interferon beta (IFNβ) through upregulation of LD formation and further enhance recruitment of NK cells in response to antitumor activity 85 .…”