Glioma-derived S100A9 polarizes M2 microglia to inhibit CD8+T lymphocytes for immunosuppression via αvβ3 integrin/AKT1/TGFβ1

Abstract

Our previous studies showed that S100A9 was overexpressed in glioma and promoted tumor growth. However, S100A9 can also be secreted by tumor cells to regulate the tumor microenvironment (TME). In this study, we aimed to explore the functions of glioma derived-S100A9 in microglial M2 polarization, resulting in inhibition of CD8+ T lymphocytes and promotion of immunosuppression. We first showed that glioma exhibited higher expression and secretion of S100A9 than astrocytes. After knocking down S100A9 in two glioma cell lines, the secretion of S100A9 was repressed. Then, the medium was collected and considered as conditioned medium (CM), which was incubated with microglia. We found that glioma-derived S100A9 drove microglial M2 polarization and increased TGFβ1 secretion. These molecular mechanisms were related to the interaction of S100A9 with αvβ3 integrin and the subsequent activation of AKT1 in microglia. Furthermore, we demonstrated that S100A9-induced M2 microglia negatively affected cell viability, IL-2 and IFN-γ secretion, together with increased early apoptosis in CD8+T lymphocytes via TGFβ1. Additionally, glioma cells were implanted into mouse brains, and we confirmed that S100A9 stimulated microglial M2 polarization, enhanced TGFβ1 levels and repressed CD8+ T lymphocytes in orthotopically transplanted tumors. In human glioma samples, S100A9 expression was positively associated with CD206 expression, but negatively correlated with CD8+T lymphocyte accumulation in the TME. Our data indicated that glioma-derived S100A9 has a promising ability to manipulate non-malignant cells and promote immune evasion in the TME, providing valuable insight into the mechanism by which S100A9 participates in the progression of glioma.