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Published on: May 21, 2019
miR-105-5p regulates PD-L1 expression and tumor immunogenicity in gastric cancer
Christos Miliotis1, Frank J Slack1
1Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Abstract:
Cancer immunotherapies targeting the interaction between Programmed death 1 (PD-1) and Programmed death ligand 1 (PD-L1) have recently been approved for the treatment of multiple cancer types, including gastric cancer. However, not all patients respond to these therapies, while some eventually acquire resistance. A partial predictive biomarker for positive response to PD-1/PD-L1 therapy is PD-L1 expression, which has been shown to be under strict post-transcriptional control in cancer. By fractionating the PD-L1 3' untranslated region (3'UTR) into multiple overlapping fragments, we identified a small 100-nucleotide-long cis-acting region as being necessary and sufficient for post-transcriptional repression of PD-L1 expression in gastric cancer. In parallel, we performed a correlation analysis between PD-L1 expression and all host miRNAs in stomach cancer patient samples. A single miRNA, miR-105-5p, was predicted to bind to the identified cis-acting 3'UTR region and to negatively correlate with PD-L1 expression. Overexpression of miR-105-5p in gastric cancer cell lines resulted in decreased expression of PD-L1, both at the total protein and surface expression levels, and induced CD8+ T cell activation in co-culture assays. Finally, we show that expression of miR-105-5p in gastric cancer is partly controlled by DNA methylation of a cancer- and germline-specific promoter of its host gene, GABRA3. Dysregulation of miR-105-5p is observed in many cancer types and this study shows the importance of this miRNA in controlling the immunogenicity of cancer cells, thus highlighting it as a potential biomarker for PD-1/PD-L1 therapy and target for combinatorial immunotherapy.
Insights
A newly discovered microRNA, miR-105-5p, represses Programmed death ligand 1 (PD-L1) in gastric cancer. This finding suggests miR-105-5p as a potential biomarker and therapeutic target for improving cancer immunotherapy response.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cancer immunotherapies targeting Programmed death 1 (PD-1) and Programmed death ligand 1 (PD-L1) show promise but have variable patient response and acquired resistance.
- Programmed death ligand 1 (PD-L1) expression is a partial predictive biomarker for immunotherapy response and is regulated post-transcriptionally in cancer.
Purpose of the Study:
- To identify the post-transcriptional regulatory mechanisms of PD-L1 expression in gastric cancer.
- To investigate the role of microRNAs in controlling PD-L1 expression and its impact on cancer immunogenicity.
Main Methods:
- Fractionation of the PD-L1 3' untranslated region (3'UTR) to identify cis-acting regulatory elements.
- Correlation analysis between PD-L1 expression and microRNA profiles in gastric cancer patient samples.
- Overexpression of miR-105-5p in gastric cancer cell lines and assessment of PD-L1 levels and T cell activation.
Main Results:
- A 100-nucleotide cis-acting region in the PD-L1 3'UTR was identified as crucial for post-transcriptional repression.
- miR-105-5p was found to bind to this region, negatively correlate with PD-L1 expression, and decrease PD-L1 levels upon overexpression.
- Overexpression of miR-105-5p enhanced CD8+ T cell activation and showed its expression is partly regulated by DNA methylation of the GABRA3 gene.
Conclusions:
- miR-105-5p plays a significant role in post-transcriptional repression of PD-L1 in gastric cancer.
- miR-105-5p represents a potential predictive biomarker and therapeutic target for enhancing PD-1/PD-L1-based immunotherapies.
- Dysregulation of miR-105-5p impacts cancer cell immunogenicity, highlighting its broader relevance in cancer research.
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