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

A. Morris, J. T. Vetto, T. Ramstad, C. J. Funatake, E. Choolun, C. Entwisle, A. D. Weinberg

Research output: Contribution to journalArticle

54 Scopus citations

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 μg 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-40 L: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.

Original languageEnglish (US)
Pages (from-to)71-80
Number of pages10
JournalBreast Cancer Research and Treatment
Volume67
Issue number1
DOIs
StatePublished - Aug 14 2001

Keywords

  • CD4 T cells
  • Costimulatory
  • Immunotherapy
  • Mammary cancer
  • OX-40

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Morris, A., Vetto, J. T., Ramstad, T., Funatake, C. J., Choolun, E., Entwisle, C., & Weinberg, A. D. (2001). Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. Breast Cancer Research and Treatment, 67(1), 71-80. https://doi.org/10.1023/A:1010649303056