title: Overcoming regulatory T-cell suppression by a lyophilized preparation of Streptococcus pyogenes.
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.
authors: Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan.
authors: Michiko
authors: M
authors: Hirayama
authors: Hiroyoshi
authors: H
authors: Nishikawa
authors: Yasuhiro
authors: Y
authors: Nagata
authors: Takemasa
authors: T
authors: Tsuji
authors: Takuma
authors: T
authors: Kato
authors: Shinichi
authors: S
authors: Kageyama
authors: Shugo
authors: S
authors: Ueda
authors: Daisuke
authors: D
authors: Sugiyama
authors: Sahoko
authors: S
authors: Hori
authors: Shimon
authors: S
authors: Sakaguchi
authors: Gerd
authors: G
authors: Ritter
authors: Lloyd J
authors: LJ
authors: Old
authors: Sacha
authors: S
authors: Gnjatic
authors: Hiroshi
authors: H
authors: Shiku
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D005122:Exudates and Transudates / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D018664:Interleukin-12 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D010844:Picibanil / Q000008:administration & dosage / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015704:CD4 Antigens; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D018664:Interleukin-12; D010844:Picibanil