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.

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

“…NF-κB cooperates with multiple oncogenic signaling pathways during cancer initiation and progression [ 204 ] and is increasingly related to high PD-L1 expression [ 73 , 177 , 205 – 207 ]. Immune escape was caused by activation of the NF-κB-PD-L1 axis [ 208 ]. The overexpression of MUC1-C caused an increased binding of NF-κB p65 to CD274 promoter and subsequently increased PD-L1 transcription in NSCLC [ 74 ].…”

Inflammation-Induced Tumorigenesis and Metastasis

“…Notably, NF-κB contributes to the suppression of anti-tumor immunity by inducing PD-L1 expression in cancer cells. For example, the NSCLCs with mutated EGFR express a higher level of PD-L1 than those with wild-type EGFR, and this phenomenon can be inhibited by the EGFR- tyrosine kinase inhibitor gefitinib in an NF-κB-dependent manner [ 227 , 228 ].…”

The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

“…The idea of targeting NF-κB as a general strategy to counteract inflammatory pathologies and NF-κB-related cancer resistance to therapy is emerging [ 93 , 94 , 95 ]. IKK inhibitors are already available and could be tested for SASP modulation.…”