Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.584626
Keywords
tumor associated macrophages; T cells; immune checkpoint inhibitors; tumor immunity; non-small-cell-lung cancer; tissue homeostasis; epithelial-mesenchymal transition; inflammation
Categories
Funding
- Associazione Italiana Ricerca sul Cancro (AIRC) [19885]
- AIRC 5 x 1000 [22757, 21147]
- Fondazione Cariplo
- Ministero Universita Ricerca (MIUR) [2017BA9LM5_001]
- Associazione Augusto per la Vita
- Associazione Medicine Rocks (ASi's laboratory)
- MIUR [2017K55HLC_006]
- Eli Lilly
- Otsuka Pharma
- Astra Zeneca
- Novartis
- BMS
- Roche
- Pfizer
- Celgene
- Incyte
- Tiziana Sciences
- Clovis
- Merck Serono
- Bayer
- MSD
- GlaxoSmithKline S.p.A.
- Spectrum Pharmaceuticals
- Blueprint Medicine
- Merck KGaA
- IPSEN
- MedImmune
- EXELISIS
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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-kappa B, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-kappa B 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-kappa B 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-kappa B signaling and PD-L1 expression is highly relevant to cancer biology and therapy.
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