Characterization of Hypoxia Signature to Evaluate the Tumor Immune Microenvironment and Predict Prognosis in Glioma Groups

Abstract

Glioma groups, including lower-grade glioma (LGG) and glioblastoma multiforme (GBM), are the most common primary brain tumor. Malignant gliomas, especially glioblastomas, are associated with a dismal prognosis. Hypoxia is a driver of the malignant phenotype in glioma groups; it triggers a cascade of immunosuppressive processes and malignant cellular responses (tumor progression, anti-apoptosis, and resistance to chemoradiotherapy), which result in disease progression and poor prognosis. However, approaches to determine the extent of hypoxia in the tumor microenvironment are still unclear. Here, we downloaded 575 LGG patients and 354 GBM patients from Chinese Glioma Genome Atlas (GGGA), and 530 LGG patients and 167 GBM patients from The Cancer Genome Atlas (TCGA) with RNA sequence and clinicopathological data. We developed a hypoxia risk model to reflect the immune microenvironment in glioma and predict prognosis. High hypoxia risk score was associated with poor prognosis and indicated an immunosuppressive microenvironment. Hypoxia signature significantly correlated with clinical and molecular features and could serve as an independent prognostic factor for glioma patients. Moreover, Gene Set Enrichment Analysis showed that gene sets associated with the high-risk group were involved in carcinogenesis and immunosuppression signaling. In conclusion, we developed and validated a hypoxia risk model, which served as an independent prognostic indicator and reflected overall immune response intensity in the glioma microenvironment.

Immune Checkpoint Targeted Therapy in Glioma: Status and Hopes

“…Herein, we further explored the role of hypoxia in the tumor immune microenvironment. Accumulating evidence indicates that hypoxia may protect tumors from immune responses through various mechanisms, including by inhibition of NK and CTL cell activity, promotion of immunosuppressive cytokines, and by enhancing immunosuppressive cells (T reg cells, TAMs, and neutrophils) (139).…”

“…Hypoxia can cause a prolonged reduction in IL-2 mRNA expression and inhibit NK cell and CTL activity. Meanwhile, hypoxia has also been shown to reduce the ability of NK cells to release IFNg, TNFa, GM-CSF, CCL3, and CCL5 (139,141). In patients with a high risk of hypoxia, CTLs and NK cells appeared to be in resting status rather than active (139), revealing that hypoxia might lead to a state of immune suppression.…”

“…It can promote the "M2" phenotype and contribute to tumor growth, immune suppression, and tumor angiogenesis (142)(143)(144). In a bioinformatic study assessing the polarization of cells in the tumor immune microenvironment, T reg cells, neutrophils, and TAMs with an "M2" phenotype increased remarkably under hypoxia (139). Besides, hypoxia also promotes the expression of TGF-b and IL-10, two well-established suppressive cytokines (139,142,145).…”

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

“…The relationship between hypoxia and immune suppression in the TME is well established and is strongly linked to numerous mechanisms described above, including the impairment of IFN-I signalling, upregulation of immune checkpoint molecules and the upregulation of extracellular adenosine [ 170 ]. Elevated hypoxic gene signatures are a major prognostic indicator in cancer patients and are frequently associated with immune-privileged (‘cold’) tumour niches [ 171 , 172 ]. Hypoxia and the induction of lactate metabolism has been reported to promote M2 polarisation of TAMs via the activation of HIF-1, Hedgehog and mTOR pathways [ 173 , 174 ].…”

Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks?

“…For example, microglia of the retina preserve a CD45 low phenotype in a light injury model and could be discriminated from infiltrating macrophages [ 74 ], while microglia of the spinal cord increased CD45 expression in a demyelination model [ 75 ]. Notably, it was demonstrated that myeloid cells showed increased expression and activity of CD45 if cells were exposed to hypoxia [ 76 ] while hypoxia is a hallmark of glioma [ 77 , 78 ]. Especially in the brain tumor context, our group clearly demonstrated a contribution of microglia to the CD45 high population in vivo, if gliomas in chimeric mice generated by head-protected irradiation were investigated [ 79 ].…”