Analysis of programmed death-ligand 1 expression in primary normal human dermal fibroblasts after DNA damage

Hum Immunol. 2018 Aug;79(8):627-631. doi: 10.1016/j.humimm.2018.05.008. Epub 2018 May 30.


Programmed cell death-1 (PD-1) and its ligand (programmed death-ligand 1, PD-L1) are key factors that regulate a cytotoxic immune reaction. Anti-PD-1 therapy provides significant clinical benefits for patients with cancer, even those with advanced-stage cancer. We have recently demonstrated that DNA damage signaling from DNA double-strand breaks (DSBs) promotes PD-L1 upregulation in cancer cells. In the present study, we aimed to investigate PD-L1 expression in primary normal human dermal fibroblasts (NHDFs) in response to DSBs. We demonstrated that PD-L1 expression in NHDFs is not upregulated after ionizing radiation (IR). In addition, interferon (IFN) regulatory factor 1 (IRF1) and signal transducer and activator of transcription 1 (STAT1) phosphorylation do not respond in NHDFs after IR. In contrast, IFNγ treatment upregulates PD-L1 and IRF1 expressions and STAT1 phosphorylation. The nonresponsiveness was also observed after treatment with other DNA-damaging agents, such as camptothecin and etoposide. Treatment with a histone deacetylase inhibitor (HDACi), which causes chromatin relaxation and restores gene silencing, upregulates PD-L1 without exogenous DNA damage; however, IR-dependent upregulation is not observed in NHDFs treated with HDACi. Taken together, our data suggest that DNA-damage signaling is insufficient for upregulating PD-L1 in NHDFs.

Keywords: Anti-PD-1 therapy; DNA damage; PD-L1 expression; Primary normal human dermal fibroblasts.

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Cells, Cultured
  • DNA Damage / immunology*
  • Dermis / pathology*
  • Etoposide / pharmacology
  • Fibroblasts / physiology*
  • Gene Expression Regulation
  • Histone Deacetylases / metabolism
  • Humans
  • Immunotherapy / methods*
  • Interferon Regulatory Factor-1 / metabolism
  • Primary Cell Culture
  • Radiation, Ionizing
  • STAT1 Transcription Factor / metabolism


  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Etoposide
  • Histone Deacetylases