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.

• Authors: Qin Luo, Naisheng Zheng, Li Jiang, Tingting Wang, Peng Zhang, Yi Liu, Peiming Zheng, Weiwei Wang, Guohua Xie, Lei Chen, Dongdong Li, Ping Dong, Xiangliang Yuan, Lisong Shen
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 11 Pg. 4000-4011 (Nov 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32798273 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Disease Models, Animal
• Disease Susceptibility
• Female
• Fluorescent Antibody Technique
• Humans
• Immunophenotyping
• Lipid Metabolism
• Lipidomics
• Macrophage Activation (genetics, immunology)
• Macrophages (immunology, metabolism)
• Mice
• Models, Biological
• Phagocytosis
• Phosphatidylinositol 3-Kinases (metabolism)
• Stomach Neoplasms (etiology, metabolism, pathology)
• T-Lymphocyte Subsets (immunology, metabolism, pathology)
• Tumor Microenvironment (genetics, immunology)
• Tumor-Associated Macrophages (immunology, metabolism, pathology)