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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.

Author information

1
Department of Microbiology and Immunology and DRU of Oral Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
2
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: miyuki.mim@tmd.ac.jp.

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.

KEYWORDS:

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

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