Hypoxia Potentiates Glioma-Mediated Immunosuppression

Abstract

Glioblastoma multiforme (GBM) is a lethal cancer that exerts potent immune suppression. Hypoxia is a predominant feature of GBM, but it is unclear to the degree in which tumor hypoxia contributes to this tumor-mediated immunosuppression. Utilizing GBM associated cancer stem cells (gCSCs) as a treatment resistant population that has been shown to inhibit both innate and adaptive immune responses, we compared immunosuppressive properties under both normoxic and hypoxic conditions. Functional immunosuppression was characterized based on production of immunosuppressive cytokines and chemokines, the inhibition of T cell proliferation and effector responses, induction of FoxP3+ regulatory T cells, effect on macrophage phagocytosis, and skewing to the immunosuppressive M2 phenotype. We found that hypoxia potentiated the gCSC-mediated inhibition of T cell proliferation and activation and especially the induction of FoxP3+T cells, and further inhibited macrophage phagocytosis compared to normoxia condition. These immunosuppressive hypoxic effects were mediated by signal transducer and activator of transcription 3 (STAT3) and its transcriptionally regulated products such as hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Inhibitors of STAT3 and HIF-1α down modulated the gCSCs' hypoxia-induced immunosuppressive effects. Thus, hypoxia further enhances GBM-mediated immunosuppression, which can be reversed with therapeutic inhibition of STAT3 and HIF-1α and also helps to reconcile the disparate findings that immune therapeutic approaches can be used successfully in model systems but have yet to achieve generalized successful responses in the vast majority of GBM patients by demonstrating the importance of the tumor hypoxic environment.

Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide

“…It has been reported that hypoxia stimulates in tumor cells the release of immunosuppressive molecules (8)(9)(10), and more recently, that it increases lung cancer cell resistance to cytotoxic T-cell-mediated lysis (11). Other studies have focused on assessing the direct effect of hypoxia on the activity of innate immune effectors rather than on hypoxia-induced adaptations of tumor cells that might endow them with resistance to immunosurveillance (12,13).…”

Genetic Analysis of Cytomegalovirus in Malignant Gliomas

“…It is known that pp65 is one of the major targets of the cellular immune response (16,17,23,24,49,59,61), and a long-term GBM survivor who underwent autologous dendritic cell vaccination was also found to mount a strong CD8 ϩ T-cell response to a pp65 immunodominant epitope (42). To assess both nucleotide and amino acid variability across the major pp65 epitope-producing domains, a 970-bp region of UL83 coding for amino acids 273 to 561 of pp65 was amplified and sequenced from seven tumor specimens that produced an amplification product (Table 2).…”

Macrophages and Microglia in Brain Malignancies

“…Treated macrophages and microglia secreted immunosuppressive cytokines (IL-10, TGF-1, IL-23) and potentiated inhibition of T cell responses. Moreover, these functions were enhanced when glioma stemlike cells were cultured under hypoxic conditions (Wei et al, 2011). Overall, these studies suggest that glioma stem-like cells acquire their central role in tumour malignancy not only through their intrinisic stem-like properties and ability to thrive in hypoxic areas of the tumour, but also by recruiting myeloid cells, recently confirmed in vivo (Yi et al, 2011), and reinforcing their pro-tumoural effects.…”