PLoS ONE (Jan 2013)

Combined TLR2/4-activated dendritic/tumor cell fusions induce augmented cytotoxic T lymphocytes.

  • Shigeo Koido,
  • Sadamu Homma,
  • Masato Okamoto,
  • Yoshihisa Namiki,
  • Kazuki Takakura,
  • Akitaka Takahara,
  • Shunichi Odahara,
  • Shintaro Tsukinaga,
  • Toyokazu Yukawa,
  • Jimi Mitobe,
  • Hiroshi Matsudaira,
  • Keisuke Nagatsuma,
  • Kan Uchiyama,
  • Mikio Kajihara,
  • Seiji Arihiro,
  • Hiroo Imazu,
  • Hiroshi Arakawa,
  • Shin Kan,
  • Hideo Komita,
  • Masaki Ito,
  • Toshifumi Ohkusa,
  • Jianlin Gong,
  • Hisao Tajiri

DOI
https://doi.org/10.1371/journal.pone.0059280
Journal volume & issue
Vol. 8, no. 3
p. e59280

Abstract

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Induction of antitumor immunity by dendritic cell (DC)-tumor fusion cells (DC/tumor) can be modulated by their activation status. In this study, to address optimal status of DC/tumor to induce efficient antigen-specific cytotoxic T lymphocytes (CTLs), we have created various types of DC/tumor: 1) un-activated DC/tumor; 2) penicillin-killed Streptococcus pyogenes (OK-432; TLR4 agonist)-activated DC/tumor; 3) protein-bound polysaccharides isolated from Coriolus versicolor (PSK; TLR2 agonist)-activated DC/tumor; and 4) Combined OK-432- and PSK-activated DC/tumor. Moreover, we assessed the effects of TGF-β1 derived from DC/tumor on the induction of MUC1-specific CTLs. Combined TLR2- and TLR4-activated DC/tumor overcame immune-suppressive effect of TGF-β1 in comparison to those single activated or un-activated DC/tumor as demonstrated by: 1) up-regulation of MHC class II and CD86 expression on DC/tumor; 2) increased fusion efficiency; 3) increased production of fusions derived IL-12p70; 4) activation of CD4(+) and CD8(+) T cells that produce high levels of IFN-γ; 5) augmented induction of CTL activity specific for MUC1; and 6) superior efficacy in inhibiting CD4(+)CD25(+)Foxp3(+) T cell generation. However, DC/tumor-derived TGF-β1 reduced the efficacy of DC/tumor vaccine in vitro. Incorporating combined TLRs-activation and TGF-β1-blockade of DC/tumor may enhance the effectiveness of DC/tumor-based cancer vaccines and have the potential applicability to the field of adoptive immunotherapy.