title: Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment.
abstract: Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients. Thus, it is important to understand the mechanisms underlying regulation of PD-L1 expression in the OSCC microenvironment. In this study, we showed that PD-L1 expression in high-grade invasive OSCC cell lines was lower than that in a low-grade invasive OSCC line and found a close correlation between PD-L1 expression and the epithelial-mesenchymal transition (EMT). PD-L1 expression was upregulated in macrophages and dendritic cells (DCs) in high-grade invasive human OSCC tissues or co-cultured with mesenchymal-phenotype OSCC cells in vitro. TLR4-inhibitory peptide successfully suppressed PD-L1 upregulation on macrophages and DCs co-cultured with mesenchymal-phenotype OSCC cells, suggesting that some EMT-induced tumour antigen is critical for PD-L1 induction on tumour-associated macrophages and DCs. Further studies are necessary to explore the impact of EMT on the tumour immune microenvironment and to identify potential biomarkers for selecting patients who might preferentially benefit from PD-1/PD-L1 blockade or immunotherapies more broadly.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Hirai
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kitahara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
authors.forename: Koroku
authors.initials: K
authors.lastname: Kato
authors.affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK.
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kawashiri
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4