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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
Quantifying the contribution of transcription factor activity, mutations and microRNAs to CD274 expression in cancer
Imke B Bruns1, Joost B Beltman2
1Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Abstract:
Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis have been remarkably successful in inducing tumor remissions in several human cancers, yet a substantial number of patients do not respond to treatment. Because this may be partially due to the mechanisms giving rise to high PD-L1 expression within a patient, it is highly relevant to fully understand these mechanisms. In this study, we conduct a bioinformatic analysis to quantify the relative importance of transcription factor (TF) activity, microRNAs (miRNAs) and mutations in determining PD-L1 (CD274) expression at mRNA level based on data from the Cancer Genome Atlas. To predict individual CD274 levels based on TF activity, we developed multiple linear regression models by taking the expression of target genes of the TFs known to directly target PD-L1 as independent variables. This analysis showed that IRF1, STAT1, NFKB and BRD4 are the most important regulators of CD274 expression, explaining its mRNA levels in 90-98% of the patients. Because the remaining patients had high CD274 levels independent of these TFs, we next investigated whether mutations associated with increased CD274 mRNA levels, and low levels of miRNAs associated with negative regulation of CD274 expression could cause high CD274 levels in these patients. We found that mutations or miRNAs offered an explanation for high CD274 levels in 81-100% of the underpredicted patients. Thus, CD274 expression is largely explained by TF activity, and the remaining unexplained cases can largely be explained by mutations or low miRNA abundance.
Insights
Transcription factor activity, mutations, and microRNAs significantly influence programmed cell death protein 1 ligand 1 (PD-L1) expression. Understanding these factors is key to improving patient response to cancer immunotherapies targeting the PD-1/PD-L1 axis.
Area of Science:
- Immunology
- Cancer Biology
- Bioinformatics
Background:
- Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis show success in cancer treatment.
- Non-response to these therapies is a significant clinical challenge, potentially linked to mechanisms driving high PD-L1 expression.
- Understanding the regulation of PD-L1 (CD274) is crucial for optimizing immunotherapy efficacy.
Purpose of the Study:
- To bioinformatically analyze the relative importance of transcription factor (TF) activity, microRNAs (miRNAs), and mutations in determining PD-L1 (CD274) mRNA expression.
- To identify key regulatory mechanisms contributing to PD-L1 expression variability in cancer patients.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) data for bioinformatic analysis.
- Developed multiple linear regression models to assess TF activity's impact on CD274 expression using TF target genes.
- Investigated the role of mutations and miRNA levels in explaining CD274 expression in cases not predicted by TF activity.
Main Results:
- IRF1, STAT1, NFKB, and BRD4 were identified as the most significant TFs regulating CD274 expression, explaining 90-98% of mRNA levels.
- For patients with CD274 levels not explained by TF activity, mutations or low miRNA abundance accounted for 81-100% of the remaining cases.
- TF activity is the primary driver of CD274 expression, with mutations and miRNAs explaining residual variability.
Conclusions:
- CD274 mRNA expression is predominantly regulated by TF activity, specifically IRF1, STAT1, NFKB, and BRD4.
- A significant portion of unexplained high CD274 expression can be attributed to genetic mutations or reduced miRNA levels.
- These findings provide critical insights into PD-L1 regulation, potentially informing strategies to overcome resistance to PD-1/PD-L1 axis inhibitors.
