Regulation of PD-L1: a novel role of pro-survival signalling in cancer

Ann Oncol. 2016 Mar;27(3):409-16. doi: 10.1093/annonc/mdv615. Epub 2015 Dec 17.


Evasion of immune system is a hallmark of cancer, which enables cancer cells to escape the attack from immune cells. Cancer cells can express many immune inhibitory signalling proteins to cause immune cell dysfunction and apoptosis. One of these inhibitory molecules is programmed death-ligand-1 (PD-L1), which binds to programmed death-1 (PD-1) expressed on T-cells, B-cells, dendritic cells and natural killer T-cells to suppress anti-cancer immunity. Therefore, anti-PD-L1 and anti-PD-1 antibodies have been used for the treatment of cancer, showing promising outcomes. However, only a proportion of patients respond to the treatments. Further understanding of the regulation of PD-L1 expression could be helpful for the improvement of anti-PD-L1 and anti-PD-1 treatments. Studies have shown that PD-L1 expression is regulated by signalling pathways, transcriptional factors and epigenetic factors. In this review, we summarise the recent progress of the regulation of PD-L1 expression in cancer cells and propose a regulatory model for unified explanation. Both PI3K and MAPK pathways are involved in PD-L1 regulation but the downstream molecules that control PD-L1 and cell proliferation may differ. Transcriptional factors hypoxia-inducible factor-1α and signal transducer and activation of transcription-3 act on the promoter of PD-L1 to regulate its expression. In addition, microRNAs including miR-570, miR-513, miR-197, miR-34a and miR-200 negatively regulate PD-L1. Clinically, it could increase treatment efficacy of targeted therapy by choosing those molecules that control both PD-L1 expression and cell proliferation.

Keywords: Akt; HIF-1Α; MAPK; NF-κB; STAT3; immune checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • B-Lymphocytes / immunology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor
  • Cell Proliferation
  • Dendritic Cells / immunology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • MicroRNAs / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism
  • Natural Killer T-Cells / immunology
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Binding / immunology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology
  • Tumor Escape / immunology*


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MicroRNAs
  • NF-kappa B
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases