Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo

Breast Cancer Res Treat. 2001 May;67(1):71-80. doi: 10.1023/a:1010649303056.

Abstract

The OX-40 receptor (OX-40R) is a member of the tumor necrosis factor receptor (TNF-R) superfamily that is expressed on activated CD4+ T cells. The OX-40R is a costimulatory molecule that induces CD4+ T cell activation when engaged by its ligand (OX-40 L; found on antigen presenting cells). In human and murine tumors, we have shown upregulation of the OX-40R on CD4+ T cells from tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC) but not on systemic CD4+ T cells, such as peripheral blood lymphocytes (PBL) or splenocytes. In order to examine potentially heightened anti-tumor immunity through enhanced costimulation when engaging OX-40R in vivo, we inoculated mice with a murine mammary cancer cell line (SM1) and then treated with a soluble form of the OX-40 L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (days 3 and 7 post-inoculation) of 100 microg soluble OX-40 L. Seven of 28 treated mice survived the lethal tumor inoculum, as compared to one of 28 control mice, demonstrating a significant survival benefit with treatment (p = 0.0136, log rank analysis). Mice that did not develop tumor by day 90 were rechallenged; all remained tumor-free. Mice were also injected with a second mammary tumor line (4T1) and treated with OX-40L:Ig with similar therapeutic results. Activation of OX-40R+ CD4+ T cells during mammary cancer priming stimulated an antitumor immune response resulting in enhanced survival and protective anti-tumor immunity. These results should have practical applications for treatment modalities for patients with breast cancer.

MeSH terms

  • Animals
  • Humans
  • Immunity, Cellular
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / mortality
  • Membrane Glycoproteins / administration & dosage*
  • Membrane Glycoproteins / immunology
  • Mice
  • Neoplasm Proteins / immunology*
  • OX40 Ligand
  • Receptors, Immunologic / immunology*
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology*
  • Tumor Necrosis Factors

Substances

  • Membrane Glycoproteins
  • Neoplasm Proteins
  • OX40 Ligand
  • Receptors, Immunologic
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • TNFRSF4 protein, human
  • TNFSF4 protein, human
  • Tnfrsf4 protein, mouse
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Tumor Necrosis Factors