Abstract
Background: Hypoxia-inducible factor 1α (HIF1A), the principal regulator of hypoxia, is involved in the suppression of antitumor immunity. We aimed to describe the T-cell exhaustion status of gliomas under different levels of HIF1A expression. Methods: In this study, 692 patients, whose data were collected from the Chinese Glioma Genome Atlas (CGGA) database, and 669 patients, whose data were collected from The Cancer Genome Atlas database, were enrolled. We further screened the data of a cohort of paired primary and recurrent patients from the CGGA dataset (n = 50). The abundance of immune cells was calculated using the transcriptome data. The association between HIF1A and T-cell exhaustion-related genes and immune cells was investigated. Results: According to the median value of HIF1A expression, gliomas were classified into low-HIF1A-expression and high-HIF1A-expression groups. The expression levels of PDL1 (CD274), FOXO1, and PRDM1 in the high-HIF1A-expression group were significantly higher in both glioblastoma (GBM) and lower-grade glioma. The abundance of exhausted T cells and B cells was significantly higher in the high-HIF1A-expression group, while that of macrophage, monocyte, and natural killer cell was significantly higher in the low-HIF1A-expression group in both GBM and lower-grade glioma. After tumor recurrence, the expression of HIF1A significantly increased, and the correlation between HIF1A expression levels and exhausted T cells and induced regulatory T cells became stronger. Conclusion: In diffuse gliomas, the levels of T-cell exhaustion-associated genes and the abundance of immune cells were elevated under high HIF1A expression. Reversing hypoxia may improve the efficacy of immunotherapy.
Highlights
As the most common primary brain tumor, the prognosis of gliomas remains dismal (Wen and Kesari, 2008)
The expression of hypoxia-inducible factor 1α (HIF1A) was higher in GBM than in lower-grade glioma in the Chinese Glioma Genome Atlas (CGGA) (p 0.008) and The Cancer Genome Atlas (TCGA) (p < 0.001) datasets
We found that the levels of exhausted, dendritic cell (DC), T helper 2 cell (Th2), and induced regulatory T cell were positively correlated with HIF1A expression, while those of natural killer cell (NK), natural killer T cell (NKT), CD8_T, CD8-naive, and γδ T cell were negatively correlated with HIF1A expression (Figure 4C)
Summary
As the most common primary brain tumor, the prognosis of gliomas remains dismal (Wen and Kesari, 2008). The recent advances in the treatment of glioma are mainly based on the patient’s diagnosis determined using molecular pathology (Louis et al, 2016). This makes it possible to develop a more precise treatment strategy. Many pioneer studies have evaluated different strategies, including immune checkpoint blockers, vaccines, and chimeric antigen receptor T cells, for treating glioma (Garcia-Fabiani et al, 2020). One important obstacle is T-cell dysfunction, induced by multiple immunosuppressive mechanisms, such as the expression of immunosuppressive factors and immune checkpoint molecules by tumors. A high proportion of exhausted T cells in tumors developed resistance to immunotherapy. We aimed to describe the T-cell exhaustion status of gliomas under different levels of HIF1A expression
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