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

Abstract

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 8 Issue 3 Pg. e59280 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23555011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-2 Antigen
• CD86 protein, human
• Cancer Vaccines
• FOXP3 protein, human
• Forkhead Transcription Factors
• MUC1 protein, human
• Mucin-1
• Proteoglycans
• TLR2 protein, human
• TLR4 protein, human
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Transforming Growth Factor beta1
• Interleukin-12
• Picibanil
• polysaccharide-K
• Interferon-gamma

Topics

• B7-2 Antigen (genetics, immunology)
• Cancer Vaccines (genetics, immunology)
• Cell Fusion
• Cell Line, Tumor
• Dendritic Cells (cytology, drug effects, immunology)
• Forkhead Transcription Factors (genetics, immunology)
• Gene Expression Regulation (drug effects)
• Humans
• Interferon-gamma (biosynthesis, immunology)
• Interleukin-12 (biosynthesis, immunology)
• Lymphocyte Activation (drug effects)
• Mucin-1 (genetics, immunology)
• Picibanil (pharmacology)
• Proteoglycans (pharmacology)
• Signal Transduction
• T-Lymphocytes, Cytotoxic (cytology, immunology)
• Toll-Like Receptor 2 (agonists, genetics, immunology)
• Toll-Like Receptor 4 (agonists, genetics, immunology)
• Transforming Growth Factor beta1 (metabolism, pharmacology)