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Glioblastoma cell differentiation trajectory predicts the immunotherapy response and overall survival of patients.

ABSTRACT: Glioblastoma (GBM) is the most common and lethal primary brain tumor. In this study, we aimed to investigate the differentiation states of GBM cells and their clinical relevance. Integrated single-cell RNA-sequencing (scRNA-seq) data and bulk RNA-seq data from GBM samples were used for analysis. Two subsets of GBM cells in distinct differentiation states were characterized, and 498 GBM cell differentiation-related genes (GDRGs) were identified. GDRGs were significantly correlated with immune regulation and metabolic pathways. We classified the GBM patients into two groups based on the expression of GDRGs in tumors and found that the cell differentiation-based classification successfully predicted patient overall survival (OS), immune checkpoint expression and likelihood of immunotherapy response in GBMs. FN1, APOE, RPL7A and GSTM2 were the 4 most significant survival-predicting GDRGs, and patients with different expression levels of each of these genes had distinct survival outcomes. Finally, a nomogram composed of the GDRG signature, age, pharmacotherapy, radiotherapy, IDH mutations and MGMT promoter methylation was generated and validated in two large GBM cohorts to predict GBM prognosis. This study highlights the significant roles of cell differentiation in predicting the clinical outcomes of GBM patients and their potential response to immunotherapy, suggesting promising therapeutic targets for GBM.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7585071 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Glioblastoma cell differentiation trajectory predicts the immunotherapy response and overall survival of patients.

Wang Zihao Z Guo Xiaopeng X Gao Lu L Wang Yu Y Ma Wenbin W Xing Bing B

Aging 20200921 18

Glioblastoma (GBM) is the most common and lethal primary brain tumor. In this study, we aimed to investigate the differentiation states of GBM cells and their clinical relevance. Integrated single-cell RNA-sequencing (scRNA-seq) data and bulk RNA-seq data from GBM samples were used for analysis. Two subsets of GBM cells in distinct differentiation states were characterized, and 498 GBM cell differentiation-related genes (GDRGs) were identified. GDRGs were significantly correlated with immune reg ...[more]

PMID: 32957084

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Project description:Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM.SignificanceImmunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM.

Dataset Information

Glioblastoma cell differentiation trajectory predicts the immunotherapy response and overall survival of patients.

Publications

Glioblastoma cell differentiation trajectory predicts the immunotherapy response and overall survival of patients.

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