PD-1 blockage delays murine squamous cell carcinoma development

Carcinogenesis. 2014 Feb;35(2):424-31. doi: 10.1093/carcin/bgt305. Epub 2013 Sep 12.


Engagement of programmed death-1 (PD-1) with its two ligands [programmed death ligand-1 (PD-L1) and PD-L2] has been associated with the suppression of tumor-reactive T cells; however, the underlying mechanism for this T-cell dysfunction is not clear. We hypothesized that PD-1 and PD-L1 signals are, in part, responsible for squamous cell carcinoma (SCC) escape from immune antitumor regulation by modulation of the tumor environment. In the present study, we used a multistage model of SCC to examine the role of PD-1/PD-L1 activation during tumor development. Tumor sites presented an increased percentage of CD4(+) and CD8(+) T cells expressing PD-1 when compared with non-tumorigenic control mice, whereas the expression of PD-L1 was particularly increased in F4/80(+) macrophages in tumor sites. Further, the systemic immune neutralization of PD-1 resulted in a decreased number and delayed incidence rate of papillomas followed by a differential expression of cytokeratins, suggesting that the PD-1-PD-L1 interaction contributes to the progression of SCC by downregulation of antitumor responses. In fact, blocking PD-1 increased the percentage of CD8(+) and CD4(+) T cells, and the levels of interferon-γ in the tumor sites. Our results indicated involvement of PD-1(+) T cells in SCC development and in the modulation of the inflammatory immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / prevention & control*
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • Immunoenzyme Techniques
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Papilloma / chemically induced
  • Papilloma / immunology*
  • Papilloma / pathology
  • Papilloma / prevention & control*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Tetradecanoylphorbol Acetate / toxicity


  • Antibodies, Monoclonal
  • Cytokines
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • 9,10-Dimethyl-1,2-benzanthracene
  • Interferon-gamma
  • Tetradecanoylphorbol Acetate