Resistance Of MFC Gastric Cancer With Re-polarized Macrophage Functional Phenotype

BackgroundMacrophages are functionally plastic cells. Type1macrophages (M1)producing type1cytokines prevent tumor from developing, whereas type2macrophages (M2) inducing type2cytokines facilitate tumor growth. Aspolarized M2subsets,tumor-associated macrophages (TAMs) show similarfunctions to M2. Furthermore, M1-inducing and M2-inducing signalsdisplayed feelings of hostility in the expression of these signals resulting intranscription of anti-tumor cytokines and chemokines.ObjectiveBased on the characteristics, we propose and demonstrate a concept ofre-polizarizing macrophages against tumor that activated macrophages canbe re-polarized into opposite functional phenotypes by microenvironmentalmodifications and then inhibit tumor growth.MethodsMouse peritoneal macrophages (PM) were treated with type1(IFN-γ,IL-12),2(IL-4, the supernatant of MFC cells and DMEM (volume ratio, 1:2. MFCS) factors or a sequentially alternate these factors. Subsequently,the conductions of TNF-α, IL-12p70and IL-10were detected in themacrophages. PM from tumor-bearing mice (TPM) and normal control(NC-PM), or aged mice (Aged-PM) and young mice (Young-PM) wereinvestigated for the stability of functional phenotypes. In another detection,we demonstrated that PM with type1or2functional activities might bereverted to display opposite functional activities and then, the conductionsof TNF-α, IL-12p70and IL-10and the activities of NO synthase (iNOS)and arginase-1(Arg-1) were detected in the macrophages. Experiments onmice, subcutaneous MFC tumors were monitored after the implantation ofMFC cells with or without type1or2macrophages.Results1. Macrophages displayed distinct functional patterns after incubationwith different factors, and a progression through multiple functionalphenotypes was induced by sequential treatment of macrophages withmultiple factors.2. Macrophages displayed a progression through multiple functionalphenotypes was induced by sequential treatment of macrophages withmultiple factors.3. Macrophage functional phenotypes established in vivo for aprolonged period of time could be altered by changing theirmicroenvironment. 4. Type2functional phenotypes could be subverted into type1phenotypes by the treatment with IL-12, in contrast, macrophages with type1functional activities may show type2functional activities after theincubation with MFCS.5. Our experiments in vivo indicated that the macrophages with type2functional phenotypes favored tumor growth, whereas those having type1functional phenotypes displated the correlates with a significant delay intumour progression.ConclusionMacrophage functional phenotypes may be partially or entirelyreversed by microenvironmental changes. Therefor, it is an extremelyimportant significance that re-polarizing macrophages, as theimmunotherapy targeting macrophages themselves but not the biologicalactivity of cytokines, metabolites and enzymes produced by themacrophages, is regarded as a fairly vital therapeutic method for tumor.