Accelerating and protective effects toward cancer growth in cGAS and FcgRIIb deficient mice, respectively, an impact of macrophage polarization

Abstract

Background: Due to the possible influence of inflammation and gut microbiota in cancers. Methods: Fc gamma receptor IIb deficient (FcGRIIb−/−) and cyclic GMP-AMP synthase deficient (cGAS−/−) mice, the model with hyperinflammation and hypo-inflammation, respectively, were subcutaneously injected with MC38 cells (a murine colon cancer cell line). Results: As such, the tumor burdens were most prominent in cGAS−/− mice, while FcGRIIb−/− mice demonstrated the least tumor sizes compared with wild-type (WT). Intra-tumoral mononuclear cells of FcGRIIb−/− (hematoxylin and eosin staining) were more prominent than other groups with the most dominant CD86-positive cells (mostly M1 proinflammatory macrophages) and the least CD206-positive cells (mostly M2 anti-inflammatory macrophages). While fecal microbiome analysis demonstrated a subtle difference among mouse strains with tumors at 24 days post-cancer injection, serum cytokines (TNF-α, IL-6, IL-1α, IFN-β, IFN-γ, IL-23, IL-12p70, GM-CSF, IL-27, and IL-17A) (fluorescence-encoded bead multiplex assay) and the expansion of immune cells in the spleens of FcGRIIb−/− mice (flow cytometry) were more prominent than others. With bone marrow-derived macrophages, prominent M1 (LPS) and M2 polarization (IL4 and cancer supernatant) in FcGRIIb−/− and cGAS−/− macrophages, respectively, were demonstrated using polymerase chain reaction and flow cytometry. The most prominent tumoricidal activity (percentage of F4/80-negative flexible780 viable dye-positive cells using flow cytometry) of LPS-stimulated FcGRIIb−/− macrophages compared with other groups supported dominant pro-inflammatory characteristics of FcGRIIb−/− macrophages. Conclusions: In conclusion, the protective and promoting effects of FcGRIIb−/− and cGAS−/− mice, respectively, against cancers are partly related to macrophage functions with a subtle correlation to fecal microbiota, and FcGRIIb inhibitors and cGAS enhancers might be helpful for cancer adjuvant treatment.