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Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures
Published on: January 9, 2019
DNA Damage Response Evaluation Provides Novel Insights for Personalized Immunotherapy in Glioma
Mu Chen1, Bingsong Huang1, Lei Zhu1
1Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Background:
DNA damage response (DDR) proficiency is the principal mechanism of temozolomide (TMZ) resistance in glioma. Accumulating evidence has also suggested the determining role of DDR in anticancer immunity. We propose that a comprehensive investigation of the DDR landscape can optimize glioma treatment.
Methods:
We identified the pronounced enrichment of DDR in TMZ-resistant glioma cells by RNA sequencing. Nine differentially expressed genes between TMZ-sensitive/resistant glioma cells were selected to construct the DDR score through lasso regression analysis. Two glioma cohorts from TCGA and CGGA were interrogated to evaluate the predictive ability of DDR score. Multiple algorithms were applied to estimate the immunotherapeutic responses of two DDR phenotypes. Immunohistochemistry was used to determine the protein levels of PD-L1 and TGFβ in glioma specimens. The oncoPredict package was employed to predict the candidate chemotherapy agents.
Results:
DDR score exhibited a robust prognostic capability in TCGA and CGGA cohorts and served as an independent predictive biomarker in glioma patients. Functional enrichment analyses revealed that high and low DDR score groups were characterized by distinct immune activity and metabolic processes. Elevated levels of infiltrating immune cells (including CD8+ T cells, CD4+ T cells, and dendritic cells) were observed in the high DDR score glioma. Further, high DDR scores correlated with increased mutation burden, up-regulated immune checkpoints, and tumor immunity activation, indicating a profound interplay between DDR score and glioma immunogenicity. In addition, PD-L1 and TGFβ were overexpressed in recurrent glioma specimens compared with primary ones. Finally, we estimated that PI3K inhibitors may serve as latent regimens for high DDR score patients.
Conclusion:
Our study highlighted the promising prognostic role of DDR score in glioma. Individual assessment of DDR status for patients with glioma may provide new clues for developing immunotherapeutic strategies.
Insights
A novel DNA damage response (DDR) score predicts glioma patient outcomes and immune response. This score may guide personalized treatment strategies, including immunotherapy and PI3K inhibitors, for glioma.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- DNA damage response (DDR) is crucial for temozolomide (TMZ) resistance in glioma.
- DDR also plays a significant role in anticancer immunity.
- Optimizing glioma treatment may involve a comprehensive analysis of the DDR landscape.
Purpose of the Study:
- To investigate the role of DDR in glioma treatment resistance and immune response.
- To develop and validate a DDR score for predicting glioma patient prognosis and therapeutic response.
- To explore potential therapeutic strategies based on DDR status.
Main Methods:
- RNA sequencing identified DDR enrichment in TMZ-resistant glioma cells.
- A DDR score was constructed using lasso regression on differentially expressed genes.
- The DDR score's predictive ability was evaluated in TCGA and CGGA glioma cohorts.
- Immunotherapeutic responses and protein levels (PD-L1, TGFβ) were assessed.
- Candidate chemotherapy agents were predicted using the oncoPredict package.
Main Results:
- The DDR score demonstrated robust prognostic capability and served as an independent predictive biomarker in glioma.
- Distinct immune activity and metabolic processes were observed between high and low DDR score groups.
- High DDR scores correlated with increased immune cell infiltration, mutation burden, and tumor immunity activation.
- PD-L1 and TGFβ were overexpressed in recurrent glioma.
- PI3K inhibitors were identified as potential treatments for high DDR score glioma.
Conclusions:
- The DDR score shows significant prognostic value in glioma.
- Individual DDR status assessment can inform the development of novel immunotherapeutic strategies for glioma patients.
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