title: Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma.
abstract: Recent clinical results for PD-1 blockade therapy have demonstrated durable tumor control with minimal immune-related adverse effects. PD-L1 is induced in non-lymphoid tissue cells and tumor cells, in addition to tissue-recruiting immune cells, under inflammatory conditions triggered by several cytokines, especially IFN-γ, and exogenous stimuli delivered by pathogen-associated molecular patterns. Receptor-mediated signaling molecules that affect the cell cycle, proliferation, apoptosis, and survival (including NF-κB, MAPK, PI3K, mTOR, and JAK/STAT) are involved in PD-L1 induction. PD-L1 expression in tumor cells is also triggered by the signals described above, but in some instances, intrinsic cell alteration associated with carcinogenesis contributes to PD-L1 induction. The tumor suppressor genes PTEN and Lkb1 and epithelial-mesenchymal transition-related molecules are also involved in the regulation of PD-L1 expression. Notably, squamous cell carcinoma of the head and neck (SCCHN) often exhibits both host immunosuppression and cytogenetic alternations of tumor cells. Precise understanding of how PD-L1 expression is controlled will allow the development of effective approaches to PD-1 blockade therapy for patients with SCCHN.
authors.affiliation: Department of Microbiology and Immunology and DRU of Oral Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Patcharee
authors.initials: P
authors.lastname: Ritprajak
authors.affiliation: Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: miyuki.mim@tmd.ac.jp.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D016328:NF-kappa B; D050791:STAT Transcription Factors; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma; D053612:Janus Kinases; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Carcinogenesis; Epithelial–mesenchymal transition; Head and neck cancer; Immune regulation; Immunotherapy; Keratinocytes; PD-L1 (B7-H1, CD274); Squamous cell carcinoma