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Oncogene. 2018 Aug;37(34):4639-4661. doi: 10.1038/s41388-018-0303-3. Epub 2018 May 16.

Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations.

Author information

1
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
2
Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
3
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
4
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden. Theodoros.Foukakis@ki.se.
5
Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden. Theodoros.Foukakis@ki.se.

Abstract

The programmed death protein 1 (PD-1) and its ligand (PD-L1) represent a well-characterized immune checkpoint in cancer, effectively targeted by monoclonal antibodies that are approved for routine clinical use. The regulation of PD-L1 expression is complex, varies between different tumor types and occurs at the genetic, transcriptional and post-transcriptional levels. Copy number alterations of PD-L1 locus have been reported with varying frequency in several tumor types. At the transcriptional level, a number of transcriptional factors seem to regulate PD-L1 expression including HIF-1, STAT3, NF-κΒ, and AP-1. Activation of common oncogenic pathways such as JAK/STAT, RAS/ERK, or PI3K/AKT/MTOR, as well as treatment with cytotoxic agents have also been shown to affect tumoral PD-L1 expression. Correlative studies of clinical trials with PD-1/PD-L1 inhibitors have so far shown markedly discordant results regarding the value of PD-L1 expression as a marker of response to treatment. As the indications for immune checkpoint inhibition broaden, understanding the regulation of PD-L1 in cancer will be of utmost importance for defining its role as predictive marker but also for optimizing strategies for cancer immunotherapy. Here, we review the current knowledge of PD-L1 regulation, and its use as biomarker and as therapeutic target in cancer.

PMID:
29765155
PMCID:
PMC6107481
DOI:
10.1038/s41388-018-0303-3
[Indexed for MEDLINE]
Free PMC Article

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