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Oral Oncol. 2015 Mar;51(3):221-8. doi: 10.1016/j.oraloncology.2014.11.014. Epub 2014 Dec 12.

Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma.

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Department of Microbiology and Immunology and DRU of Oral Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:


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.


Carcinogenesis; Epithelial–mesenchymal transition; Head and neck cancer; Immune regulation; Immunotherapy; Keratinocytes; PD-L1 (B7-H1, CD274); Squamous cell carcinoma

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