Abstract
Dendritic cells (DC) are a promising cell type for cancer vaccines due to their high immunostimulatory capacity. However, improper maturation of DC prior to treatment may account for the limited efficacy of DC vaccine clinical trials. Latent Membrane Protein-1 (LMP1) of Epstein-Barr virus was examined for its ability to mature and activate DC as a gene-based molecular adjuvant for DC vaccines. DC were transduced with an adenovirus 5 vector (Ad5) expressing LMP1 under the control of a Tet-inducible promoter. Ad5-LMP1 was found to mature and activate both human and mouse DC. LMP1 enhanced in vitro migration of DC toward CCL19, as well as in vivo migration of DC to the inguinal lymph nodes of mice following intradermal injection. LMP1-transduced DC increased T cell proliferation in a Pmel-1 adoptive transfer model and enhanced survival in B16-F10 melanoma models. LMP1-DC also enhanced protection in a vaccinia-Gag viral challenge assay. LMP1 induced high levels of IL-12p70 secretion in mouse DC when compared to standard maturation protocols. Importantly, LMP1-transduced human DC retained the capacity to secrete IL-12p70 and TNF in response to DC restimulation. In contrast, DC matured with Monocyte Conditioned Media-Mimic cocktail (Mimic) were impaired in IL-12p70 secretion following restimulation. Overall, LMP1 matured and activated DC, induced migration to the lymph node, and generated high levels of IL-12p70 in a murine model. We propose LMP1 as a promising molecular adjuvant for DC vaccines.
Highlights
Dendritic cells (DC) are professional antigen presenting cells that play a central role in the adaptive immune response
Immunotherapy with monocyte-derived DC is a promising approach for the treatment of cancer and chronic viral infections such as HIV
The chemical PGE2 is known to disrupt the ability of monocyte derived DC to secrete IL-12p70 in response to restimulation [15, 16, 18, 34]
Summary
Dendritic cells (DC) are professional antigen presenting cells that play a central role in the adaptive immune response. A small number of DC can induce a robust immune response [1, 2], making ex vivo DC an attractive reagent for cancer immunotherapy [3]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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