Lipid Accumulation In Tumor-associated Macrophages Induces M2 Polarization And Pro-tumor Potential In Gastric Cancer

Objective: Tumor-associated macrophages(TAMs)play an important role for tumor initiation and progression.Recently,several studies have shown that lipid metabolism was involved in regulating the function of tumor-associated immune cells.However,the effect of lipid metabolism on TAMs is still unclear.This study intends to clarify the effect and detailed mechanism of lipid metabolism on TAMs polarization in gastric cancer,which will provide new ideas for the crosstalk between gastric cancer cells and TAMs.Methods: 1.Flow cytometry and immunohistochemistry were used to detect the phenotype and distribution of TAMs in human gastric cancer tissues and animal gastric cancer models.The lipophilic fluorescent dye BODIPY 493/503 was used to detect the lipid amount in TAMs.2.TAMs with different lipid content from MFC tumor-bearing mice were sorted and characterized the phenotype profiles.Functional assays were further conducted to investigate the pro-tumor potential of lipid-laid TAMs.3.We will also explore the detailed molecular mechanism of lipid accumulation on the function of TAMs.Results: 1.Here we report that a substantial proportion of TAMs in patients with gastric cancer negatively correlated with the survival period.Higher amounts of lipid contents were found in TAMs,compared to macrophages from tumor-free mice and healthy individuals.The TAMs with lipid accumulation characterised by M2-like phenotype with high expression of CD206 and low expression of MHCII.2.TAMs with high lipid present pro-tumor function,showing low phagocytosis ability,suppression of T cell proliferation,and pro-migration potential of MFC cells.3.In our study,lipid accumulation in TAMs might be caused by increased uptake of extracellular lipids from tumor cells or tumor microenvironment,which induces the increased expression of gamma isoform of phosphoinositide 3-kinase(PI3K?),highly expressed in myeloid cells,polarizing to an M2-like profiling.Furthermore,we demonstrate that this effect of lipid accumulation on TAMs to M2-like polarization could be reversed by the inhibitor of PI3K?.Pharmacological targeting PI3K? in high-lipid TAMs with a selective inhibitor,like IPI549,restore the functional activity of macrophages and substantially enhance the effects of phagocytosis and anti-tumor immunity activity.Conclusions: Collectively,our work thus discovers a critical phenomenon on TAMs and identifies a mechanism of communication between macrophages and tumor cells in gastric cancer.This cross-talk most probably evolves to be engaged in gastric cancer growth by manipulating the lipid levels in TAMs.