Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients’ survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body’s effective anti-glioma immune response.

In human gliomas, anti-tumor T cell responses are inhibited through induction of local and systemic immunosuppression. Immune checkpoint blockade is proving to be a success in several types of cancers. However, many studies reported that the treatment of glioblastoma patients with anti-CTLA-4 or anti-PD-1 has no survival benefit compared to standard chemotherapy. This study aimed to investigate the expression and role of VISTA, a newly described immune checkpoint regulator, in human gliomas. mRNA expression was assessed in a total of 87 samples from glioma patients. 57 glioma tissues were taken at different grades. 20 peripheral blood mononuclear cells (PBMC) samples were taken before surgery and ten after surgery, all from the same set of patients. As for the control, ten specimens of PBMC were taken from healthy donors. Protein expression using immunohistochemistry was performed for 30 patients. The Cancer Genome Atlas (TCGA) data set, was also used to investigate VISTA expression through analysis of RNA-seq data of 667 glioma patients. In the Moroccan cohort, VISTA gene expression was significantly upregulated in glioma tissues related to PBMC of healthy donors. This high expression was specific to patient tissues since VISTA expression in PBMC was low when assessed either before or after surgery. Besides, VISTA exhibited higher expression levels in grade III/IV relative to grade I/II glioma patients. Interestingly, VISTA correlated positively with PD-1 expression. PD-1 also showed elevated expressions in higher glioma grades. The TCGA cohort corroborated these observations. Indeed, VISTA was also found to be strongly expressed in high grades. It was positively correlated with other critical immune checkpoints. Finally, increased VISTA transcript levels were associated with weak overall survival of glioma patients. Our study highlighted a correlation between high levels of VISTA expression and poor prognosis in glioma patients. VISTA might be involved in glioma progression and could be considered as a possible new therapeutic target, especially in advanced gliomas.

Glioma is the most prevalent primary brain tumor. Immune checkpoint blockade has made a great stride in mending patient’s clinical outcome for multiple types of cancers. However, PD-1, CTLA-4, or VEGF blockade exhibited only poor outcome in glioma patients. This study aimed to explore the expression and role of IgSF11, an emerging immune checkpoint and a ligand of VISTA, in human gliomas. IgSF11 mRNA expression was assessed in human glioma patients at different grades using 2 independent cohorts, a set of 52 Moroccan samples, including 20 glioma tissues, 22 PBMC samples taken before and 10 PBMC samples taken after surgery; and a series of 667 patients from TCGA. In parallel, immunohistochemistry was performed to evaluate IgSF11 protein staining. IgSF11 gene expression was significantly upregulated in high grade glioma tissues, compared to low grade. IgSF11 protein also showed a significant expression in low and high-grade gliomas. Interestingly, IgSF11 expression seemed to correlate positively with other critical immune checkpoints such as PD1, PDL-1, VISTA, and surprisingly negatively with CTLA-4. Although, T cell markers appeared higher in advanced gliomas, T cell-produced pro-inflammatory genes showed similar expression levels, highly likely because of the potent immunosuppressive microenvironment. Indeed, increased expression of IgSF11 in advanced human gliomas associated with a poor overall survival. Our data strongly suggest that IgSF11 is an immune checkpoint, which is upregulated in advanced human gliomas and contributes to the immunosuppressive state resulting in a poor clinical outcome in glioma patients. IgSF11 could be considered as a possible promising therapeutic target in advanced human gliomas.

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