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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism*
  • Carcinoma, Squamous Cell / metabolism*
  • Epithelial Cells / metabolism*
  • Epithelial-Mesenchymal Transition / physiology
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Interferon-gamma / metabolism
  • Janus Kinases / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NF-kappa B / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / metabolism


  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • NF-kappa B
  • STAT Transcription Factors
  • Tumor Suppressor Proteins
  • Interferon-gamma
  • Janus Kinases
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase Kinases