Palmitic Acid combined with γ-interferon inhibits gastric cancer progression by modulating macrophages polarization via the TLR4 pathway

Abstract

Abstract Background Tumor-associated macrophages (TAMs) constitute the main infiltrating immune cells in the solid tumor microenvironment. Amounting studies have analyzed the anti-tumor effect on immune response induced by (TLR) agonists, such as Lipopolysaccharide (LPS), γ-interferon (γ-IFN), and Palmitic Acid (PA). However, their combination treatment for gastric cancer (GC) has been unilluminated. Methods We investigated the relevance of macrophage polarization and the effect of PA and γ-IFN in GC in vitro and in vivo. M1 and M2 macrophage-associated markers were measured by real-time quantitative PCR and Flow Cytometry, and the activation level of the TLR4 signaling pathways was evaluated by Western Blot. The effect of PA and γ-IFN on the proliferation, migration, and invasion of gastric cancer cells (GCC), was evaluated by Cell-Counting-Kit-8, transwell assays, and wound-healing assays. In vivo animal models were used to verify the effect of PA and γ-IFN on tumor progression, and the M1 and M2 macrophage markers, CD8 + T lymphocytes, regulatory T cells (Treg), and the myeloid-derived suppressor cells (MDSCs) in tumor tissues were analyzed by Flow Cytometry and Immunohistochemical (IHC). Results Our results showed that this combination strategy enhanced M1-like macrophages and diminished M2-like macrophages through the TLR4 signaling pathway in vitro. In addition, the combination strategy impairs the proliferative and migratory activity of GCC in vitro and in vivo. While the anti-tumor effect was abrogated by using the TAK-424 (a specific TLR-4 signaling pathway inhibitor) in vitro. Conclusions The combination of Palmitic Acid and γ-interferon inhibits gastric cancer progression by modulating macrophages polarization via the TLR4 pathway