Human blood myeloid and plasmacytoid dendritic cells cross activate each other and synergize in inducing NK cell cytotoxicity

Human blood dendritic cells (DCs) hold great potential for use in anticancer immunotherapies. CD1c+ myeloid DCs and plasmacytoid DCs (pDCs) have been successfully utilized in clinical vaccination trials against melanoma. We hypothesize that combining both DC subsets in a single vaccine can further improve vaccine efficacy. Here, we have determined the potential synergy between the two subsets in vitro on the level of maturation, cytokine expression, and effector cell induction. Toll-like receptor (TLR) stimulation of CD1c+ DCs induced cross-activation of immature pDCs and vice versa. When both subsets were stimulated together using TLR agonists, CD86 expression on pDCs was increased and higher levels of interferon (IFN)-α were produced by DC co-cultures. Although the two subsets did not display any synergistic effect on naive CD4+ and CD8+ T cell polarization, CD1c+ DCs and pDCs were able to complement each other's induction of other immune effector cells. The mere presence of pDCs in DC co-cultures promoted plasma cell differentiation from activated autologous B cells. Similarly, CD1c+ DCs, alone or in co-cultures, induced high levels of IFN-γ from allogeneic peripheral blood lymphocytes or activated autologous natural killer (NK) cells. Both CD1c+ DCs and pDCs could enhance NK cell cytotoxicity, and interestingly DC co-cultures further enhanced NK cell-mediated killing of an NK-resistant tumor cell line. These results indicate that co-application of human blood DC subsets could render DC-based anticancer vaccines more efficacious.