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

Autor: Peng Zhang, Yi Liu, Lei Chen, Li Jiang, Qin Luo, Naisheng Zheng, Guohua Xie, Weiwei Wang, Lisong Shen, Peiming Zheng, Ping Dong, Dongdong Li, Tingting Wang, Xiangliang Yuan
Rok vydání: 2020
Předmět:
0301 basic medicine
Gene isoform
Cancer Research
tumor‐associated macrophages
Phagocytosis
T cell
Fluorescent Antibody Technique
Models
Biological
Immunophenotyping
03 medical and health sciences
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Basic and Clinical Immunology
Downregulation and upregulation
Stomach Neoplasms
T-Lymphocyte Subsets
Cell Line
Tumor
Tumor-Associated Macrophages
Extracellular
medicine
Tumor Microenvironment
Animals
Humans
KEGG
PI3K/AKT/mTOR pathway
polarization
Chemistry
Macrophages
gastric cancer
lipid accumulation
General Medicine
Original Articles
Macrophage Activation
Lipid Metabolism
tumor immunity
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Cell Transformation
Neoplastic
Oncology
Tumor progression
030220 oncology & carcinogenesis
Lipidomics
Cancer research
Female
Original Article
Disease Susceptibility
Zdroj: Cancer Science
ISSN: 1349-7006
Popis: 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.
TAM with high lipid levels were characterized by M2‐like polarized profiling. Lipid accumulation in TAM was caused by increased uptake of extracellular lipids from tumor cells. Pharmacological targeting of PI3Kγ in high‐lipid TAM with a selective inhibitor, like IPI549, restores the functional activity of TAM and substantially enhances anti–tumor immunity activity in vitro and in vivo.
Databáze: OpenAIRE
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