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Induction of Anti-Mammary Cancer Immunity by Engaging the OX-40 Receptor in Vivo

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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-40L; 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-40L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (days 3 and 7 post-inoculation) of 100μg soluble OX-40L. 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 anti-tumor 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.

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Authors and Affiliations

  1. Department of Surgery, Section of Surgical Oncology, Oregon Health Sciences University, Oregon, USA

    Arden Morris & John T. Vetto

  2. Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, USA

    Trygg Ramstad, Castle J. Funatake & Andrew D. Weinberg

  3. Cantab Pharmaceuticals, Tude, Cambridge, UK

    Esther Choolun & Claire Entwisle

Authors
  1. Arden Morris
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  2. John T. Vetto
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  3. Trygg Ramstad
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  4. Castle J. Funatake
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  5. Esther Choolun
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  6. Claire Entwisle
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  7. Andrew D. Weinberg
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Morris, A., Vetto, J.T., Ramstad, T. et al. Induction of Anti-Mammary Cancer Immunity by Engaging the OX-40 Receptor in Vivo. Breast Cancer Res Treat 67, 71–80 (2001). https://doi.org/10.1023/A:1010649303056

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  • DOI: https://doi.org/10.1023/A:1010649303056

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