IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

Br J Cancer. 2015 Apr 28;112(9):1501-9. doi: 10.1038/bjc.2015.101. Epub 2015 Mar 31.


Background: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear.

Methods: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed.

Results: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01).

Conclusions: Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • B7-H1 Antigen / metabolism*
  • Blotting, Western
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Proliferation
  • Disease Progression
  • Female
  • Flow Cytometry
  • Humans
  • Immunoenzyme Techniques
  • Interferon-gamma / pharmacology*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Mice, Inbred C57BL
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology*
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / immunology
  • Peritoneal Neoplasms / metabolism*
  • Peritoneal Neoplasms / secondary*
  • Prognosis
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • B7-H1 Antigen
  • Interferon-gamma