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 |
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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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