Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model

Int J Oncol. 2009 Oct;35(4):741-9. doi: 10.3892/ijo_00000387.

Abstract

The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, B7-H1 and B7-DC, has been suggested to play an important role in tumor evasion from host immunity. Pancreas cancer patients with B7-H1 expression have a poor prognosis. B7-H1 blocking has been shown to inhibit the development of a subcutaneous tumor from a pancreas cancer cell line. In this study, we investigated the effects of B7-DC as well as B7-H1 blockade in vivo in a murine pancreatic cancer model. Pancreatic cancer cells (Panc02) were inoculated in the pancreas of C57BL/6 mice. Five weeks later, tumor sizes were measured and the mice bearing appropriate size of tumors received the following treatments. Blocking antibodies against B7-H1 or B7-DC (200 microg) were administered 3 times/week for 3 weeks. Cells infiltrating the tumors were characterized by immunohistochemistry. Effects of antibodies on cytokine and FoxP3 expression were examined by quantitative RT-PCR. In vitro cultured Panc02 cells expressed B7-H1 upon IFN-gamma stimulation. However, expression of B7-H1 and B7-DC was found mainly on CD45-positive infiltrating cells and rarely on cancer cells in vivo. Treatment with both antibodies significantly decreased tumor growth in vivo. B7-DC blockade decreased the levels of IL-10 and FoxP3, suggesting that regulatory systems are mainly inhibited at the tumor site. B7-H1 blockade increased the levels of IFN-gamma and FoxP3. Collectively, blocking of B7-H1 or B7-DC efficiently induced regression of pre-established pancreatic cancers by up-regulating IFN-gamma production and down-regulating IL-10 production at the tumor site.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • Antibodies, Blocking / pharmacology*
  • Antigens, CD / analysis
  • Antigens, Differentiation / immunology*
  • Antigens, Differentiation, Myelomonocytic / analysis
  • Antineoplastic Agents / pharmacology*
  • B7-1 Antigen / drug effects*
  • B7-1 Antigen / immunology
  • B7-H1 Antigen
  • CD11b Antigen / analysis
  • CD4 Antigens / analysis
  • CD8 Antigens / analysis
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Forkhead Transcription Factors / genetics
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-10 / genetics
  • Leukocyte Common Antigens / analysis
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Peptides / antagonists & inhibitors*
  • Peptides / immunology
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger / metabolism
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Escape / drug effects*

Substances

  • Antibodies, Blocking
  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Differentiation, Myelomonocytic
  • Antineoplastic Agents
  • B7-1 Antigen
  • B7-H1 Antigen
  • CD11b Antigen
  • CD4 Antigens
  • CD68 protein, mouse
  • CD8 Antigens
  • Cd274 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger
  • Interleukin-10
  • Interferon-gamma
  • Leukocyte Common Antigens
  • Ptprc protein, mouse