Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades

Abstract

BackgroundGlioma is the most common type of primary brain tumor in adults. Patients with the most malignant form have an overall survival time of <16 months. Although considerable progress has been made in defining the adapted therapeutic strategies, measures to counteract tumor escape have not kept pace, due to the developed resistance of malignant glioma. In fact, identifying the nature and role of distinct tumor-infiltrating immune cells in glioma patients would decipher potential mechanisms behind therapy failure.MethodsWe integrated into our study glioma transcriptomic datasets from the Cancer Genome Atlas (TCGA) cohort (154 GBM and 516 LGG patients). LM22 immune signature was built using CIBERSORT. Hierarchical clustering and UMAP dimensional reduction algorithms were applied to identify clusters among glioma patients either in an unsupervised or supervised way. Furthermore, differential gene expression (DGE) has been performed to unravel the top expressed genes among the identified clusters. Besides, we used the least absolute shrinkage and selection operator (LASSO) and Cox regression algorithm to set up the most valuable prognostic factor.ResultsOur study revealed, following gene enrichment analysis, the presence of two distinct groups of patients. The first group, defined as cluster 1, was characterized by the presence of immune cells known to exert efficient antitumoral immune response and was associated with better patient survival, whereas the second group, cluster 2, which exhibited a poor survival, was enriched with cells and molecules, known to set an immunosuppressive pro-tumoral microenvironment. Interestingly, we revealed that gene expression signatures were also consistent with each immune cluster function. A strong presence of activated NK cells was revealed in cluster 1. In contrast, potent immunosuppressive components such as regulatory T cells, neutrophils, and M0/M1/M2 macrophages were detected in cluster 2, where, in addition, inhibitory immune checkpoints, such as PD-1, CTLA-4, and TIM-3, were also significantly upregulated. Finally, Cox regression analysis further corroborated that tumor-infiltrating cells from cluster 2 exerted a significant impact on patient prognosis.ConclusionOur work brings to light the tight implication of immune components on glioma patient prognosis. This would contribute to potentially developing better immune-based therapeutic approaches.

A comprehensive pancancer analysis reveals the potential value of RAR-related orphan receptor C (RORC) for cancer immunotherapy

“…Notably, RORC expression had prognostic value in some cancers, especially KIRC, LGG, and MESO. Consistently, Ait Ssi et al ( Ait Ssi et al, 2021 ) found that RORC expression is upregulated in LGG patients with a poor prognosis. In conclusion, RORC expression can be an important regulator of cancers and RORC has prognostic value in some cancers.…”

The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis

“…Chraa et al reviewed the tumor microenvironment and its infiltration by distinct T lymphocyte subpopulations 33 . This report explained the association of these different subtypes with cancer progression 33 , 34 . However, treatment with several cytokines, including IFN-γ, IL-2, IL-4, and IL-6, did not raise VISTA expression in tumor cells 35 .…”

The Role of Myeloid Cells in GBM Immunosuppression

“…Several studies have advocated that pro-inflammatory M1 phenotype—associated with upregulation of CD115 and Siglec and consecutive production of IL-1β, IL-6, or IFN-γ—is critical for tumor eradication ( 39 ), especially since M1 phenotype has been reported to correlate with favorable survival outcomes in many human cancers ( 47 ). However, this trend appears inconsistent in glioma as inhibitory immune checkpoints such as PD-1, CTLA-4 and TIM-3 are consistently upregulated in M1/M2 GAMs which have been shown to significantly decrease patient prognosis ( 48 , 49 ). Mice study has revealed that disruption of GBM-derived IL-6, known to induce myeloid PD-L1, reduces local and systemic myeloid-driven immunosuppression ( 50 ).…”