Silencing IDO in dendritic cells: A novel approach to enhance cancer immunotherapy in a murine breast cancer model

Authors

  • Xiufen Zheng,

    Corresponding author
    1. Department of Surgery, University of Western Ontario, London, Canada
    2. Department of Pathology, University of Western Ontario, London, Ontario
    3. Lawson Health Research Institute, London, Canada
    • Department of Surgery, University of Western Ontario, London, Canada
    Search for more papers by this author
  • James Koropatnick,

    1. Department of Pathology, University of Western Ontario, London, Ontario
    2. Department of Oncology, University of Western Ontario, London, Canada
    3. Department of Microbiology and Immunology, University of Western Ontario, London, Canada
    4. Department of Physiology and Pharmacology, University of Western Ontario, London,Canada
    5. Lawson Health Research Institute, London, Canada
    6. London Regional Cancer Program, London, Canada
    Search for more papers by this author
  • Di Chen,

    1. Department of Pathology, University of Western Ontario, London, Ontario
    Search for more papers by this author
  • Thomas Velenosi,

    1. Department of Physiology and Pharmacology, University of Western Ontario, London,Canada
    Search for more papers by this author
  • Hong Ling,

    1. Department of Chemistry, University of Western Ontario, London, Canada
    Search for more papers by this author
  • Xusheng Zhang,

    1. Department of Surgery, University of Western Ontario, London, Canada
    Search for more papers by this author
  • Nan Jiang,

    1. Department of Surgery, University of Western Ontario, London, Canada
    Search for more papers by this author
  • Benjamin Navarro,

    1. Department of Pathology, University of Western Ontario, London, Ontario
    Search for more papers by this author
  • Thomas E. Ichim,

    1. Medistem Inc, San Diego, CA
    Search for more papers by this author
  • Bradley Urquhart,

    1. Department of Physiology and Pharmacology, University of Western Ontario, London,Canada
    Search for more papers by this author
  • Weiping Min

    Corresponding author
    1. Department of Surgery, University of Western Ontario, London, Canada
    2. Department of Pathology, University of Western Ontario, London, Ontario
    3. Department of Oncology, University of Western Ontario, London, Canada
    4. Lawson Health Research Institute, London, Canada
    5. London Regional Cancer Program, London, Canada
    • 339 Windermere Road, University Hospital C9-136, London, Ontario, N6A 5A5, Canada
    Search for more papers by this author
    • Tel.: 1-519-663-2985, Fax: 1-519-663-3295


Abstract

Cancer immunotherapeutic agents (vaccines) in the form of antigen-loaded dendritic cells (DCs) reached an important milestone with the recent approval of Provenge, the first DC vaccine for treatment of prostate cancer. Although this heralds a new era of tumor immunotherapy, it also highlights the compelling need to optimize such DC-based therapies as they are increasingly tested and used to treat human patients. In this study we sought to augment and enhance the antitumor activity of a DC-based vaccine using siRNA to silence expression of immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in DCs. We report here that DCs loaded with tumor antigens, but with siRNA-silenced IDO expression, were introduced into 4T1 breast tumor-bearing mice, the treatment: (i) lengthened the time required for tumor onset, (ii) decreased tumor size compared to tumors grown for equal lengths of time in mice treated with antigen-loaded DCs without IDO silencing and (iii) reduced CD4+ and CD8+ T cell apoptosis. Furthermore, immunization with IDO-silenced DCs enhanced tumor antigen-specific T cell proliferation and CTL activity, and decreased numbers of CD4+CD25+Foxp3+ Treg. This study provides evidence to support silencing of immunosuppressive genes (IDO) as an effective strategy to enhance the efficacy of DC-based cancer immunotherapeutic.

Ancillary