PD-L1 alteration in lung cancer affects tumorigenicity lung tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA720411 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14165601.fastq.gz | Fastqsanger.gz | |||
| SRR14165602.fastq.gz | Fastqsanger.gz | |||
| SRR14165603.fastq.gz | Fastqsanger.gz | |||
| SRR14165604.fastq.gz | Fastqsanger.gz | |||
| SRR14165605.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T cells, allowing tumors to suppress T cell activity 1-3. Clinical trials utilizing monoclonal antibodies that disrupt the PD-1/PD-L1 immune checkpoint have yielded remarkable results, with PD-1 immunotherapy approved as a first-line therapy for human lung cancer patients 4-6. Despite significant progress in targeting this pathway, the mechanisms through which PD-L1 is upregulated in non-small cell lung cancer (NSCLC) and other tumor types remain incompletely understood. Here we used CRISPR-based screening to identify regulators of PDL1 in human lung cancer cells, revealing potent induction of PD-L1 levels upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the integrated stress response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5¢ UTR, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention.
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Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
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