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

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.

Figure 1

Mechanisms of PD-L1 expression through NF-κB. (A) Oncogene-related mechanisms. MUC1 and EGFR up-regulate PD-L1 expression by activating NF-κB pathway. These pathways are intertwined with EMT. HPV modulates PD-L1 expression triggering STING that in turn activates NF-κB. (B) Inflammatory cytokine-related mechanisms. Tumor-infiltrating immune cells can produce several cytokines regulating PD-L1 expression. Two well-known cytokines acting via NF-κB pathway are TNFα produced by TAMs and IFN-γ produced by tumor infiltrating T and NK cells. (C) Drug- and stress-related mechanisms. Different drugs act on NF-κB transcriptional activity (e.g., Palblociclib). Stress response to UVR activates NF-κB, thus mediating PD-L1 up-regulation. Blue arrows indicate activation of NF-kB pathway; black arrows indicate NF-κB-mediated PD-L1 up-regulation; red T-arrows indicate negative regulation. EGFR, Epidermal Growth Factor Receptor; EMT, Epithelial-Mesenchymal Transition; HPV, Human Papilloma Virus; IFN, Interferon; JAK, Janus Kinase; MUC1, Mucin 1; NK, Natural Killer; PD-L1, Programmed Cell Death Protein 1 Ligand; RB, Retinoblastoma; STAT, Signal Transducer and Activator of Transcription; STING, Stimulator of Interferon Genes; TAMs, Tumor Associated Macrophages; TNF, Tumor Necrosis Factor; UVR, ultraviolet radiation.