Cancer Res Treat.  2020 Apr;52(2):530-542. 10.4143/crt.2019.440.

A Radiosensitivity Gene Signature and PD-L1 Status Predict ClinicalOutcome of Patients with Glioblastoma Multiforme in The CancerGenome Atlas Dataset

• Jang BS
• Kim IA

• KMID: 2500338
• DOI: http://doi.org/10.4143/crt.2019.440

Abstract

Purpose
Combination of radiotherapy and immune checkpoint blockade such as programmed death- 1 (PD-1) or programmed death-ligand 1 (PD-L1) blockade is being actively tested in clinical trial. We aimed to identify a subset of patients that could potentially benefit from this strategy using The Cancer Genome Atlas (TCGA) dataset for glioblastoma (GBM).
Materials and Methods
A total of 399 cases were clustered into radiosensitive versus radioresistant (RR) groups based on a radiosensitivity gene signature and were also stratified as PD-L1 high versus PD-L1 low groups by expression of CD274 mRNA. Differential and integrated analyses with expression and methylation data were performed. CIBERSORT was used to enumerate the immune repertoire that resulted from transcriptome profiles.
Results
We identified a subset of GBM, PD-L1-high-RR group which showed worse survival compared to others. In PD-L1-high-RR, differentially expressed genes (DEG) were highly enriched for immune response and mapped into activation of phosphoinositide 3-kinase–AKT and mitogen-activated protein kinase (MAPK) signaling pathways. Integration of DEG and differentially methylated region identified that the kinase MAP3K8-involved in T-cell receptor signaling was upregulated and BAI1, a factor which inhibits angiogenesis, was silenced. CIBERSORT showed that a higher infiltration of the immune repertoire, which included M2 macrophages and regulatory T cells.
Conclusion
Taken together, PD-L1-high-RR group could potentially benefit from radiotherapy combined with PD-1/PD-L1 blockade and angiogenesis inhibition.

Keyword

Glioblastoma; Radiosensitivity; PD-L1, Radiation; Angiogenesis

Figure

• 

  Fig. 1. Kaplan-Meier curves for overall survival among four combinatorial groups in RT-treated patients (A) and in no RTtreated ones (B). To test our hypothesis, four combinatorial groups were re-grouped into two groups (PD-L1-high-RR vs. others). Again, Kaplan-Meier curves for overall survival comparing two groups are depicted in RT-treated patients (C) and no RT-treated ones (D), respectively. p-value was estimated by the log-rank test. RT, radiation therapy; PD-L1, programmed death-ligand 1; RR, radioresistant; RS, radiosensitive.

• 

  Fig. 2. (A) Heatmap comparing the mean fraction of immune cells between the samples in the PD-L1-high-RR and the others groups, showing the differential 30 gene expression pattern. Rows list each of the 30 genes, and columns show each sample. The expression level was normalized between –10 and 10, represented by the colors (green to red). Gene set enrichment analysis and the relationship between differentially expressed genes and methylation-regulated genes. The top 20 enriched biologic processes (B) and pathways (C) are shown. The x-axis indicates a–log10 FDR, the red line represents the ratio of genes in that pathway, and the number in parenthesis is the number of common genes in that pathway. In the starburst plot (D), log10 (FDR-corrected p-value) is plotted for DNA methylation (x axis) and gene expression (y axis). The degree of change (log2 multiple) is indicated by color (red and green). RT, radiation therapy; PD-L1, programmed death-ligand 1; RR, radioresistant; MGMT, O6 -methylguanine-DNA methyltransferase; IDH, isocitrate dehydrogenase; FDR, false discovery rate.

• 

  Fig. 3. In the starburst plot (D), log10 (FDR-corrected p-value) is plotted for DNA methylation (x axis) and gene expression (y axis). The degree of change (log2 multiple) is indicated by color (red and green). RT, radiation therapy; PD-L1, programmed death-ligand 1; RR, radioresistant; MGMT, O6 -methylguanine-DNA methyltransferase; IDH, isocitrate dehydrogenase; FDR, false discovery rate. (A) From CIBERSORT, the normalized mean fraction of each of the immune cells found within samples in the PD-L1-high-RR and the others groups are demonstrated in the bar plot. (B) Results from the another deconvolutional tool, quanTIseq, are presented in bar graphs indicating the relative normalized mean fraction of immune cells between the PD-L1-high-RR and others groups. PD-L1, programmed death-ligand 1; RR, radioresistant.

Reference

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