Bioinformatic profiling identifies an immune-related risk signature for glioblastoma

Cheng, Wen; Ren, Xiufang; Zhang, Chuanbao; Cai, Jinquan; Liu, Yang; Han, Sheng; Wu, Anhua

doi:10.1212/wnl.0000000000002770

Cited by 174 publications

(172 citation statements)

References 35 publications

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“…Although typically used to define immunosuppressive TAMs, we find that the number of cells expressing CD163 in glioma tissue is significantly increased in patients with both grade I astrocytoma and GBM. This is supported by previous findings showing that the number of tumor associated macrophages may be less significant than their gene expression and corresponding functions, 64,65 and suggests that identification of additional markers is required to define a phenotype associated with immunosuppressive functions. This model is supported by the various redundant mechanisms of immunosuppression in the TME, including soluble GBM tumor cell derived factors such as TGFβ, 66 LDH5, 5 IL-10, 67 and IDO.…”

Section: Discussionsupporting

confidence: 84%

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

et al. 2018

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Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue.Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

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Section: Discussionsupporting

confidence: 84%

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

et al. 2018

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“…However, EV uptake by a certain cell may not only depend on the presence of specific cellular receptors, but in the case of bridging uptake mechanisms, also on the availability of adaptor ligands, either secreted by the recipient or donor cell, or by other cells in the microenvironment. Here, we show that CCL18 functions as bridging adaptor for GBM EVs, and CCL18 expression has been identified as an important prognostic factor in GBM [90]. Recently, it was shown that EVs can also be decorated by autotaxin resulting in binding to integrins expressed on cell surfaces [32].…”

Section: Discussionmentioning

confidence: 95%

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

Berenguer

Lagerweij

Zhao

et al. 2018

J of Extracellular Vesicle

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Cancer cells release extracellular vesicles (EVs) that contain functional biomolecules such as RNA and proteins. EVs are transferred to recipient cancer cells and can promote tumour progression and therapy resistance. Through RNAi screening, we identified a novel EV uptake mechanism involving a triple interaction between the chemokine receptor CCR8 on the cells, glycans exposed on EVs and the soluble ligand CCL18. This ligand acts as bridging molecule, connecting EVs to cancer cells. We show that glioblastoma EVs promote cell proliferation and resistance to the alkylating agent temozolomide (TMZ). Using in vitro and in vivo stem-like glioblastoma models, we demonstrate that EV-induced phenotypes are neutralised by a small molecule CCR8 inhibitor, R243. Interference with chemokine receptors may offer therapeutic opportunities against EV-mediated cross-talk in glioblastoma.

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“…GO analysis showed that up-regulation genes were enriched in immune response and inflammatory response pathways. Moreover, it reported that immune response may play important role in GBM recently [17]. IKBIP (I kappa B kinase interacting protein) is a novel p53 target gene with proapoptotic function which is consistence with P53 pathway of GSEA results.…”

Section: Discussionmentioning

confidence: 99%

A three-gene signature for prognosis in patients with MGMT promoter-methylated glioblastoma

et al. 2016

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Glioblastoma is the most malignant tumor and has high mortality rate. The methylated prompter of MGMT results in chemotherapy sensitivity for these patients. However, there are still other factors that affected the prognosis for the glioblastoma patients with similar MGMT methylation status. We developed a signature with three genes screened from the whole genome mRNA expression profile from Chinese Glioma Genome Atlas (CGGA) and RNAseq data from The Cancer Genome Atlas (TCGA). Patients with MGMT methylation in low risk group had longer survival than those in high risk group (median overall survival 1074 vs. 372 days; P = 0.0033). Moreover, the prognostic value of the signature was significant difference in cohorts stratified by MGMT methylation and chemotherapy (P=0.0473), while there is no significant difference between low and high risk group or unmethylated MGMT patients without chemotherapy. Multivariate analysis indicated that the risk score was an independent prognosis factor (P = 0.004). In conclusion, our results showed that the signature has prognostic value for patients with MGMT promoter-methylated glioblastomas based on bioinformatics analysis.

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Bioinformatic profiling identifies an immune-related risk signature for glioblastoma

Abstract: We profiled the immune status in glioma and established a local immune signature for GBM, which could independently identify patients with a high risk of reduced survival, indicating the relationship between prognosis and local immune response.

Cited by 174 publications

References 35 publications

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

A three-gene signature for prognosis in patients with MGMT promoter-methylated glioblastoma

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