title: 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.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan. shigeo_koido@jikei.ac.jp
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koido
authors.forename: Sadamu
authors.initials: S
authors.lastname: Homma
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Namiki
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takakura
authors.forename: Akitaka
authors.initials: A
authors.lastname: Takahara
authors.forename: Shunichi
authors.initials: S
authors.lastname: Odahara
authors.forename: Shintaro
authors.initials: S
authors.lastname: Tsukinaga
authors.forename: Toyokazu
authors.initials: T
authors.lastname: Yukawa
authors.forename: Jimi
authors.initials: J
authors.lastname: Mitobe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsudaira
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagatsuma
authors.forename: Kan
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Mikio
authors.initials: M
authors.lastname: Kajihara
authors.forename: Seiji
authors.initials: S
authors.lastname: Arihiro
authors.forename: Hiroo
authors.initials: H
authors.lastname: Imazu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arakawa
authors.forename: Shin
authors.initials: S
authors.lastname: Kan
authors.forename: Hideo
authors.initials: H
authors.lastname: Komita
authors.forename: Masaki
authors.initials: M
authors.lastname: Ito
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Jianlin
authors.initials: J
authors.lastname: Gong
authors.forename: Hisao
authors.initials: H
authors.lastname: Tajiri
mesh_terms: D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D002459:Cell Fusion; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology; D010844:Picibanil / Q000494:pharmacology; D011509:Proteoglycans / Q000494:pharmacology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051940:B7-2 Antigen; C497964:CD86 protein, human; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C060192:MUC1 protein, human; D018396:Mucin-1; D011509:Proteoglycans; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12; D010844:Picibanil; C010770:polysaccharide-K; D007371:Interferon-gamma
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