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.
Highlights
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) and attractive vectors for cancer immunotherapy [1]
Fusion of DCs and tumor cells We developed various types of DC/tumor by alternating fusion partners as follows: immature DCs (Imm-DCs) fused with PANC/Mock (Imm/ Mock); OK-DCs fused with PANC/Mock (OK/Mock); PSK-DCs fused with PANC/Mock (PSK/Mock); OPK-DCs fused with PANC/Mock (OPK/Mock); Imm-DCs fused with PANC/transforming growth factor (TGF)-b (Imm/TGF-b); OK-DCs fused with PANC1/TGF-b (OK/TGFb); PSK-DCs fused with PANC/TGF-b (PSK/TGF-b); and OPK
To ensure the delivery of a ‘‘cell drug’’ that is safe, reproducible, and efficient, fetal calf serum (FCS)-independent tumor cells that could grow with human plasma protein fraction (PPF) were first established, as FCS has a possible risk of infection with pathogens of prion diseases for clinical use [11]
Summary
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) and attractive vectors for cancer immunotherapy [1]. Penicillin-killed and lyophilized preparations of a low-virulence strain (Su) of Streptococcus pyogenes (OK-432) act as a TLR4 agonist and can activate DCs, macrophages, neutrophils, T cells, and NK cells by inducing multiple cytokines such as interleukin (IL)-12 and interferon (IFN)-c and polarizing T cell responses to a Th1dominant state [8]. Both OK-432 and PSK are good manufacturing practice (GMP) grade agents and have been used clinically as biological response modifiers [9,10]. Effects of DC/tumor derived immune-suppressive factors such as transforming growth factor (TGF)-b1 on CTL induction were assessed
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