Regulation of PD-L1 Expression by NF-κB in Cancer

Front Immunol. 2020 Nov 25;11:584626. doi: 10.3389/fimmu.2020.584626. eCollection 2020.

Abstract

Immune checkpoints are inhibitory receptor/ligand pairs regulating immunity that are exploited as key targets of anti-cancer therapy. Although the PD-1/PD-L1 pair is one of the most studied immune checkpoints, several aspects of its biology remain to be clarified. It has been established that PD-1 is an inhibitory receptor up-regulated by activated T, B, and NK lymphocytes and that its ligand PD-L1 mediates a negative feedback of lymphocyte activation, contributing to the restoration of the steady state condition after acute immune responses. This loop might become detrimental in the presence of either a chronic infection or a growing tumor. PD-L1 expression in tumors is currently used as a biomarker to orient therapeutic decisions; nevertheless, our knowledge about the regulation of PD-L1 expression is limited. The present review discusses how NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-κB directly induces PD-L1 gene transcription by binding to its promoter, and it can also regulate PD-L1 post-transcriptionally through indirect pathways. These processes, which under conditions of cellular stress and acute inflammation drive tissue homeostasis and promote tissue healing, are largely dysregulated in tumors. Up-regulation of PD-L1 in cancer cells is controlled via NF-κB downstream of several signals, including oncogene- and stress-induced pathways, inflammatory cytokines, and chemotherapeutic drugs. Notably, a shared signaling pathway in epithelial cancers induces both PD-L1 expression and epithelial-mesenchymal transition, suggesting that PD-L1 is part of the tissue remodeling program. Furthermore, PD-L1 expression by tumor infiltrating myeloid cells can contribute to the immune suppressive features of the tumor environment. A better understanding of the interplay between NF-κB signaling and PD-L1 expression is highly relevant to cancer biology and therapy.

Keywords: T cells; epithelial-mesenchymal transition; immune checkpoint inhibitors; inflammation; non-small-cell-lung cancer; tissue homeostasis; tumor associated macrophages; tumor immunity.

Publication types

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

MeSH terms

  • B7-H1 Antigen / immunology*
  • Epithelial-Mesenchymal Transition / immunology
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Immunity / immunology
  • Inflammation / immunology
  • NF-kappa B / immunology*
  • Neoplasms / immunology*
  • Signal Transduction / immunology

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • NF-kappa B