Overcoming regulatory T-cell suppression by a lyophilized preparation of Streptococcus pyogenes

Authors

  • Michiko Hirayama,

    1. Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan
    2. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Hiroyoshi Nishikawa,

    Corresponding author
    1. Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
    • Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Yasuhiro Nagata,

    1. Department of Surgery, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan
    Search for more papers by this author
  • Takemasa Tsuji,

    1. Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    Search for more papers by this author
  • Takuma Kato,

    1. Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Mie, Japan
    Search for more papers by this author
  • Shinichi Kageyama,

    1. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
    Search for more papers by this author
  • Shugo Ueda,

    1. Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
    Search for more papers by this author
  • Daisuke Sugiyama,

    1. Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
    Search for more papers by this author
  • Sahoko Hori,

    1. Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan
    2. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
    Search for more papers by this author
  • Shimon Sakaguchi,

    1. Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
    Search for more papers by this author
  • Gerd Ritter,

    1. Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    Search for more papers by this author
  • Lloyd J. Old,

    1. Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    Search for more papers by this author
  • Sacha Gnjatic,

    1. Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    Search for more papers by this author
  • Hiroshi Shiku

    Corresponding author
    1. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan
    • Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan
    Search for more papers by this author

Full correspondence: Dr. Hiroyoshi Nishikawa, Experimental Immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Fax: +81-6-6879-4464

e-mail: nisihiro@ifrec.osaka-u.ac.jp

Additional correspondence: Sacha Gnjatic, Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

e-mail: gnjatics@mskcc.org

Additional correspondence: Hiroshi Shiku, Departments of Cancer Vaccine and Immuno-Gene Therapy, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

e-mail: shiku@clin.medic.mie-u.ac.jp

Abstract

Cancer vaccines have yet to yield clinical benefit, despite the measurable induction of humoral and cellular immune responses. As immunosuppression by CD4+CD25+ regulatory T (Treg) cells has been linked to the failure of cancer immunotherapy, blocking suppression is therefore critical for successful clinical strategies. Here, we addressed whether a lyophilized preparation of Streptococcus pyogenes (OK-432), which stimulates Toll-like receptors, could overcome Treg-cell suppression of CD4+ T-cell responses in vitro and in vivo. OK-432 significantly enhanced in vitro proliferation of CD4+ effector T cells by blocking Treg-cell suppression and this blocking effect depended on IL-12 derived from antigen-presenting cells. Direct administration of OK-432 into tumor-associated exudate fluids resulted in a reduction of the frequency and suppressive function of CD4+CD25+Foxp3+ Treg cells. Furthermore, when OK-432 was used as an adjuvant of vaccination with HER2 and NY-ESO-1 for esophageal cancer patients, NY-ESO-1–specific CD4+ T-cell precursors were activated, and NY-ESO-1–specific CD4+ T cells were detected within the effector/memory T-cell population. CD4+ T-cell clones from these patients had high-affinity TCRs and recognized naturally processed NY-ESO-1 protein presented by dendritic cells. OK-432 therefore inhibits Treg-cell function and contributes to the activation of high-avidity tumor antigen-specific naive T-cell precursors.

Ancillary