Glioma cancer stem cells induce immunosuppressive macrophages/microglia

Abstract

Macrophages (MΦs)/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 MΦs/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated MΦ inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-β1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of MΦ/microglia phagocytosis, induction of MΦ/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-β1, and MIC-1, cytokines known to recruit and polarize the MΦs/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the MΦ/microglia to an M2 phenotype, inhibited MΦ/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-β1 by the MΦs/microglia, and enhanced the capacity of MΦs/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 MΦs/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.

Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice

“…This change in the immune response of microglia is in agreement with the pathologic results in vivo [33,34]. This phenomenon might be induced by glioma stem cells, which are considered to contribute to the conversion of microglia from classically activated M1 to immunosuppressive M2 phenotypes, which impede the phagocytic ability of microglia [35].…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

“…A critical therapeutic advantage in using cytotoxins via CED is that they cause death of targeted cells (70). Even though the GBM tumor environment is highly immunosuppressive (98,99) and patients with GBM are immunosuppressed (100, 101), a large number of killed tumor cells provides a "danger signal" and evokes effective antitumor immune responses. Our published (41) and unpublished observations suggested, and another study demonstrated directly (102), the existence of effective immune responses in preclinical studies with cytotoxic proteins.…”

Stem cell technology and engineering for cancer treatment

“…However, studies have shown that cancer stem cells have the ability to evade the immune system (Schneider et al, 2011;Wei et al, 2010;Wu et al, 2010). Therefore, new cancer treatment therapy to target cancer stem cells by enhancing the immune system is important and necessary.…”