Glioma cancer stem cells induce immunosuppressive macrophages/microglia

Macrophages (M Phi s)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of M Phi s/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated M(1) inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-beta 1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of M Phi/microglia phagocytosis, induction of M Phi/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-beta 1, and MIC-1, cytokines known to recruit and polarize the M Phi s/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the M Phi/microglia to an M2 phenotype, inhibited M Phi/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-beta 1 by the M Phi s/microglia, and enhanced the capacity of M Phi s/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive M Phi s/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.