Abstract
Dendritic cell (DC) vaccines for cancer immunotherapy have been actively developed to improve clinical efficacy. In our previous report, monocyte−derived DCs induced by interleukin (IL)−4 with a low−adherence dish (low−adherent IL-4−DCs: la−IL-4−DCs) improved the yield and viability, as well as relatively prolonged survival in vitro, compared to IL-4−DCs developed using an adherent culture protocol. However, la−IL-4−DCs exhibit remarkable cluster formation and display heterogeneous immature phenotypes. Therefore, cluster formation in la−IL-4−DCs needs to be optimized for the clinical development of DC vaccines. In this study, we examined the effects of cluster control in the generation of mature IL-4−DCs, using cell culture vessels and measuring spheroid formation, survival, cytokine secretion, and gene expression of IL-4−DCs. Mature IL-4−DCs in cell culture vessels (cluster−controlled IL-4−DCs: cc−IL-4−DCs) displayed increased levels of CD80, CD86, and CD40 compared with that of la−IL-4−DCs. cc−IL-4−DCs induced antigen−specific cytotoxic T lymphocytes (CTLs) with a human leukocyte antigen (HLA)−restricted melanoma antigen recognized by T cells 1 (MART−1) peptide. Additionally, cc−IL-4−DCs produced higher levels of IFN−γ, possessing the CTL induction. Furthermore, DNA microarrays revealed the upregulation of BCL2A1, a pro−survival gene. According to these findings, the cc−IL-4−DCs are useful for generating homogeneous and functional IL-4−DCs that would be expected to promote long−lasting effects in DC vaccines.
Highlights
Dendritic cells (DCs) are antigen−presenting cells (APCs) that play a central role in the immune response to pathogenic antigens and autologous tumor antigens [1]
To optimize the maturation conditions, we evaluated the effect of seeding density and total cell number on cluster formation and IL-4 DCs phenotype
We developed a standardized protocol for manufacturing DC vaccines by controlling cluster formation
Summary
Dendritic cells (DCs) are antigen−presenting cells (APCs) that play a central role in the immune response to pathogenic antigens and autologous tumor antigens [1]. DCs take up tumor antigens and migrate into the lymph nodes, where antigens are presented through major histocompatibility complexes on DCs to naïve T cells via T−cell receptors. The naïve T cells primed with DCs become cytotoxic T lymphocytes (CTLs) and memory. DC−based cancer vaccines, which induce tumor antigen−specific immune responses, have been evaluated in clinical trials and other studies against various cancer types [4,5,6]. Clinical trials using DC vaccines to target tumor−specific antigens combined with immune checkpoint inhibitors (such as tremelimumab and nivolumab) have attracted attention in recent years [7,8]. DC vaccination could provide a therapeutic with a low incidence of grade 3 and 4 adverse events [4,11]
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