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Updated: Aug 5, 2025
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
The screening of compounds regulating PD-L1 transcriptional activity in a cell functional high-throughput manner
Lanxin Zhang1, Hexin Li1, Jingchao Liu2
1Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Abstract:
Immune checkpoints are protein molecules expressed on the immune cell membrane, which regulate the immune system to kill tumor cells. As an essential immune checkpoint, overexpressed PD-1 on tumor cells could inhibit T-cell activation after being bonded to PD-1. Due to this inhibitory effect, T-cell proliferation and cytokine secretion are suppressed, leading to immune escape of tumor cells. Here, we established a high-throughput method based on cell function screening technology to screen drugs regulating PD-L1 expression in tumor cells at the transcriptional level. After two screening rounds, 12 compounds that enhanced PD-L1 transcription while seven weakened were sorted out among 1018 FDA-approved drugs. Finally, a tumor cell line was used to verify the upregulation of endogenous PD-L1 expression for a drug named "vorinostat," a histone deacetylation inhibitor, after the two rounds of optional selection. Therefore, our research provides another perspective for using "vorinostat" in treating tumors and offers a convenient method to detect the transcriptional expression of other intracellular proteins besides PD-L1.
Insights
Researchers screened FDA-approved drugs to find those affecting PD-L1 expression in tumor cells. Vorinostat was identified as a drug that upregulates PD-L1, offering new therapeutic perspectives for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoints, like PD-1, regulate immune responses against tumors.
- Overexpressed PD-1 on tumor cells inhibits T-cell activation, promoting tumor immune escape.
- Targeting PD-L1 expression is a key strategy in cancer immunotherapy.
Purpose of the Study:
- To establish a high-throughput screening method for identifying drugs that modulate PD-L1 transcription in tumor cells.
- To discover novel therapeutic agents for cancer treatment by regulating PD-L1 expression.
- To provide a versatile method for assessing transcriptional expression of intracellular proteins.
Main Methods:
- Development of a cell function screening assay for high-throughput drug screening.
- Screening of 1018 FDA-approved drugs in two rounds to identify modulators of PD-L1 transcription.
- Validation of drug-induced PD-L1 upregulation using a tumor cell line and vorinostat.
Main Results:
- Identified 12 compounds that enhanced PD-L1 transcription and 7 that weakened it from 1018 FDA-approved drugs.
- Confirmed vorinostat, a histone deacetylation inhibitor, upregulates endogenous PD-L1 expression in tumor cells.
- Demonstrated the efficacy of the high-throughput screening method for transcriptional regulation analysis.
Conclusions:
- Vorinostat presents a potential therapeutic option for cancer treatment by upregulating PD-L1.
- The developed screening platform offers a convenient approach for evaluating transcriptional regulation of intracellular proteins, including PD-L1.
- This research provides new insights into targeting immune checkpoints for enhanced anti-tumor immunity.
