PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor

Wang, Zhiliang; Li, Guanzhang; Wang, Qiangwei; Bao, Zhaoshi; Wang, Zheng; Zhang, Chuanbao; Jiang, Tao

doi:10.1080/2162402x.2018.1541535

Cited by 39 publications

(39 citation statements)

References 44 publications

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“…Similarly, PD-L2 expression across 1357 glioma samples conferred shorter survival times compared to low expressing counterparts. In addition, PD-L2 expression positively correlated with T-regulatory signatures indicating the functional role of PD-L2 in enhancing glioma immunosuppression(34). A similar study of 976 brain glioma samples showed the same functional implications of PD-L1 expression, whereby WHO grade IV gliomas had higher levels of PD-L1 expression compared to grade II and III gliomas.…”

mentioning

confidence: 70%

Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype

Joseph

Finlay

et al. 2019

Preprint

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Glioblastoma Multiforme is a highly aggressive brain malignancy commonly refractory to classical and novel chemo-, radio-and immuno-therapies, with median survival times of ~15 months following diagnosis. Poor immunological responses exemplified by the downregulation of T-cell activity, and upregulation of immunosuppressive cells within the tumour micro-environment have limited the effectiveness of immunotherapy in GBM to date. Here we show that GBM cells express a large repertoire of inhibitory checkpoint ligands. Furthermore, GBM cells with an enhanced stem cell-like phenotype exhibit heightened levels of inhibitory checkpoint ligands, compared to non-stem cell-like GBM cells. Understanding how GBM modulates an extensive repertoire of immune checkpoint ligands and the functional consequence on immune evasion are necessary to develop effective immuno-therapeutics.

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confidence: 70%

Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype

Joseph

Finlay

et al. 2019

Preprint

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“…ing CGGA sequencing data, we calculated a transcriptional Notch pathway activation signature using GSVA. GSVA is a technique for characterizing activation of pathways from gene expression dataset 25 and is commonly used to identify expression enrichments between different samples/ group of samples [38][39][40][41] . In order to verify the credibility of the Notch score, correlation analysis was performed between our enrichment calculation and consensus Notch signaling genes.…”

Section: Results Establishment Of Notch Activation Signature In Clinimentioning

confidence: 99%

A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma

Khan

Tsiampali

et al. 2020

Sci Rep

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The Notch signaling network determines stemness in various tissues and targeting signaling activity in malignant brain cancers by gamma-secretase inhibitors (GSI) has shown promising preclinical success. However, the clinical translation remains challenging due to severe toxicity side effects and emergence of therapy resistance. Better anti-Notch directed therapies, specifically directed against the tumor promoting Notch receptor 1 signaling framework, and biomarkers predicting response to such therapy are of highest clinical need. We assessed multiple patient datasets to probe the clinical relevance Notch1 activation and possible differential distribution amongst molecular subtypes in brain cancers. We functionally assessed the biological effects of the first-in-human tested blocking antibody against Notch1 receptor (brontictuzumab, BRON) in a collection of glioma stem-like cell (GSC) models and compared its effects to genetic Notch1 inhibition as well as classical pharmacological Notch inhibitor treatment using gamma-secretase inhibitor MRK003. We also assess effects on Wingless (WNT) stem cell signaling activation, which includes the interrogation of genetic WNT inhibition models. Our computed transcriptional Notch pathway activation score is upregulated in neural stem cells, as compared to astrocytes; as well as in GSCs, as compared to differentiated glioblastoma cells. Moreover, the Notch signature is clinical predictive in our glioblastoma patient discovery and validation cohort. Notch signature is significantly increased in tumors with mutant IDH1 genome and tumors without 1p and 19q co-deletion. In GSCs with elevated Notch1 expression, BRON treatment blocks transcription of Notch pathway target genes Hes1/Hey1, significantly reduced the amount of cleaved Notch1 receptor protein and caused significantly impairment of cellular invasion. Benchmarking this phenotype to those observed with genetic Notch1 inhibition in corresponding cell models did result in higher reduction of cell invasion under chemotherapy. BRON treatment caused signs of upregulation of Wingless (WNT) stem cell signaling activity, and vice versa, blockage of WNT signaling caused induction of Notch target gene expression in our models. We extend the list of evidences that elevated Notch signal expression is a biomarker signature declaring stem cell prevalence and useful for predicting negative clinical course in glioblastoma. By using functional assays, we validated a first in man tested Notch1 receptor specific antibody as a promising drug candidate in the context of neuro oncology and propose biomarker panel to predict resistance and therapy success of this treatment option. We note that the observed phenotype seems only in part due to Notch1 blockage and the drug candidate leads to activation of off target signals. Further studies addressing a possible emergence of therapy resistance due to WNT activation need to be conducted. We further validated our 3D disease modeling technology to be of benefit for drug development projects.

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“…PD-1/PD-Ls axis is the most important immune checkpoints in cancer immunity, but whether PD-1/PD-Ls have notable influence on LGG biology is largely unknown. We have noticed two studies presented by Prof. Jiang's group reported that PD-L1 and PD-L2 were correlated with WHO grade system and poor prognosis in gliomas and GBM, as well as PD-L2 also had promising prognostic value in LGG [9,10]. In this research, we systematically evaluated PD-1/PD-Ls expression and their prognostic values in…”

Section: Discussionmentioning

confidence: 98%

“…Previously, PD-L1 and PD-L2 (PD-Ls) expression have been revealed to be correlated with poor prognosis of glioma [9,10]. As we all known, two main glioma subtypes,…”

Section: Introductionmentioning

confidence: 99%

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Mei

Cai

et al. 2020

Preprint

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Background: Immune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet. Methods:A total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation inLGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.Results: PD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in differentLGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration.Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes. Conclusions:High expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

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PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor

Cited by 39 publications

References 44 publications

Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype

Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype

A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

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