Abstract
Dendritic cell (DC)-based vaccination is a promising immunotherapeutic strategy for cancer. However, clinical trials have shown only limited efficacy, suggesting the need to optimize protocols for human DC vaccine preparation. In this study, we systemically compared five different human DC vaccine maturation protocols used in clinical trials: (1) a four-cytokine cocktail (TNF-α, IL-6, IL-1β, and PGE2); (2) an α-DC-cytokine cocktail (TNF-α, IL-1β, IFN-α, IFN-γ, and poly I:C); (3) lipopolysaccharide (LPS)/IFN-γ; (4) TNF-α and PGE2; and (5) TriMix (mRNAs encoding CD40L, CD70, and constitutively active Toll-like receptor 4 electroporated into immature DCs). We found that the four-cytokine cocktail induced high levels of costimulatory and HLA molecules, as well as CCR7, in DCs. Mature DCs (mDCs) matured with the four-cytokine cocktail had higher viability than those obtained with the other protocols. Based on these features, we chose the four-cytokine cocktail protocol to further improve the immunizing capability of DCs by introducing exogenous genes. We showed that introducing exogenous Bcl-2 increased DC survival. Furthermore, introducing IL-12p70 rescued the inhibition of IL-12 secretion by PGE2 without impairing the DC phenotype. Introducing both Bcl-2 and IL-12p70 mRNAs into DCs induced enhanced cytomegalovirus pp65-specific CD8+ T cells secreting IFN-γ and TNF-α. Taken together, our data suggest that DC matured by the four-cytokine cocktail combined with exogenous Bcl-2 and IL-12p70 gene expression represents a promising approach for clinical applications in cancer immunotherapy.
Highlights
Dendritic cell (DC)-based vaccination can be used to induce host antitumor immunity and has shown promising clinical efficacy against some tumors (Yu et al, 2004; De Vleeschouwer et al, 2008; Cho et al, 2012; Mitchell et al, 2015; Erhart et al, 2018; Reap et al, 2018)
The mature DC (mDC) induced by the four-cytokine cocktail showed a significantly higher level of all six surface markers (CD40, CD80, CD83, CD86, HLAABC, and HLA-DR) compared with those induced by the other protocols (Figure 1B)
MDCs induced by the α-DC-cytokine cocktail protocol had high expression levels of CD40, CD80, and CD86 but low levels of CD83, and failed to upregulate HLA-ABC and HLA-DR (Figure 1B)
Summary
Dendritic cell (DC)-based vaccination can be used to induce host antitumor immunity and has shown promising clinical efficacy against some tumors (Yu et al, 2004; De Vleeschouwer et al, 2008; Cho et al, 2012; Mitchell et al, 2015; Erhart et al, 2018; Reap et al, 2018). At least five different human DC vaccine maturation protocols have been used in clinical trials These protocols include a four-cytokine cocktail (TNF-α, IL-6, IL-1β, and PGE2) (Lee et al, 2002; Scandella et al, 2004; Batich et al, 2017); an α-DC cytokine cocktail (TNF-α, IL-1β, IFN-α, IFN-γ, and poly I:C) (Mailliard et al, 2004; Lee et al, 2008; Park et al, 2011; Akiyama et al, 2012); LPS plus IFN-γ (Dohnal et al, 2007), TNF-α plus PGE2 (Holtl et al, 1999); and TriMix DC (electroporation of a mixture of CD40L, CD70, and a constitutively active form of Toll-like receptor 4 (caTLR4) mRNAs into immature DCs) (Van Nuffel et al, 2012; Benteyn et al, 2013). This enables the resulting DC vaccines to present antitumor antigens and prime T cells
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