Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer

Abstract

Heterotypic interactions between tumor cells and macrophages can enable tumor progression and hold potential for the development of therapeutic interventions. However, the communication between tumors and macrophages and its mechanism are poorly understood. Here, we find that tumor‐associated macrophages (TAM) from tumor‐bearing mice have high amounts of lipid as compared to macrophages from tumor‐free mice. TAM also present high lipid content in clinical human gastric cancer patients. Functionally, TAM with high lipid levels are characterized by polarized M2‐like profiling, and exhibit decreased phagocytic potency and upregulated programmed death ligand 1 (PD‐L1) expression, blocking anti–tumor T cell responses to support their immunosuppressive function. Mechanistically, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identifies the specific PI3K pathway enriched within lipid‐laid TAM. Lipid accumulation in TAM is mainly caused by increased uptake of extracellular lipids from tumor cells, which leads to the upregulated expression of gamma isoform of phosphoinositide 3‐kinase (PI3K‐γ) polarizing TAM to M2‐like profiling. Correspondingly, a preclinical gastric cancer model is used to show pharmacological targeting of PI3K‐γ in high‐lipid TAM with a selective inhibitor, IPI549. IPI549 restores the functional activity of macrophages and substantially enhances the phagocytosis activity and promotes cytotoxic‐T‐cell‐mediated tumor regression. Collectively, this symbiotic tumor‐macrophage interplay provides a potential therapeutic target for gastric cancer patients through targeting PI3K‐γ in lipid‐laden TAM.

Lipid droplets: could they be involved in cancer growth and cancer–microenvironment communications?

“…Intracellular accumulation of lipids increases the oxidative metabolism and activates the immunosuppressive pathways in MDSCs [12]. A similar effect is demonstrated by TAMs that are enriched with lipids in a tumor environment and acquire immunosuppressive properties [13], because TAMs express elevated levels of lipid transport receptors supporting LD formation [14]. In other words, lipid-dependent fatty acid metabolism controls the immunosuppressive phenotype of TAMs.…”

“…In other words, lipid-dependent fatty acid metabolism controls the immunosuppressive phenotype of TAMs. Therefore, inhibition of lipid uptake and LD formation by a specific inhibitor of fatty acid synthase C75 [14] and/or degradation of LDs enables inhibiting the suppressive function of TAMs [15]. Moreover, systemic immune changes were prevented by G-CSF blockade, revealing a remarkable plasticity in the systemic immune state [16].…”

Lipid-Laden Macrophages and Inflammation in Atherosclerosis and Cancer: An Integrative View

“…As a consequence, the contribution of LDL to the generation of lipid-laden TAMs appears to be minute. Thus, stimulation of the fluid-phase pinocytosis in macrophages by the low pH of the intratumoral environment would rather stimulate FA uptake and ensuing accumulation of triglycerides and glycerophospholipids in the lipid droplets, as it has been observed in TAMs (136,137). In analogy to the strong association between the formation of cholesteryl ester-filled macrophage foam cells and atherosclerosis progression, the formation of neutral lipid droplets in TAMs has been found to correlate with various types of cancer (84), and more recently with the human colorectal cancer progression (134).…”

Metabolic Reprogramming in Gastric Cancer: Trojan Horse Effect

“…Especially, M2 macrophage can exacerbate the FA β-oxidation and promote the 5-fluorouracil (5-FU) chemoresistance in GC ( 66 ). The lipid restores the activity and substantially enhances the phagocytosis of TAMs, leading to promoted cytotoxic T-cell-mediated tumor regression in GC ( 67 ). In addition, miR-130b, the correspondent of the M2-TAMs in GC ( 68 ), is associated with lipid metabolism and 5-FU resistance and even can activate PI3K ( 69 – 71 ), which is potentially a new chemotherapeutic target by interfering immune cell metabolism in TAMs.…”