Diverse functional activity of CD83(+) monocyte-derived dendritic cells and the implications for cancer vaccines

Antigen-loaded dendritic cells (DCs) provide key regulatory signals to T ce lls during a developing antitumor response. In addition to providing costim ulation, mature DC provides cytokine and chemokine signals that can define the T1 vs T2 nature of the antitumor T-cell response as well as whether T c ells engage in direct interactions with tumor cells. In serum-free culture conditions that hasten the differentiation of monocytes into mature DCs, ce rtain agents, such as CD40L, accelerate phenotypic maturation (e.g., CD83 a nd costimulatory molecule expression) without influencing the acquisition o f Dc1/Dc2 characteristics. In contrast, exposure to serum-free medium and i nterferon-gamma (IFN-gamma) rapidly influences CD83(+) DCs to secrete high levels of IL-12, IL-6, and MIP-1 beta, and promotes Dc1 differentiation. In contrast, CD83(+) DCs matured in serum-free medium in the absence of IFN-g amma, or in the presence of calcium signaling agents, prostaglandin-E2, or IFN-alpha, produce no IL-12, scant IL-6, and prodigious IL-8, MDC, and TARC , and promote Dc2 differentiation. T cells sensitized via IL-12-secreting, peptide-pulsed DCs secrete cytokines when subsequently exposed to relevant peptide-pulsed antigen-presenting cells (APCs) or to HLA-compatible tumor c ells endogenously expressing the peptide. In contrast, T cells sensitized v ia IL-12 nonsecreting DC were limited to antigenic reactivation through APC contact rather than tumor cell contact. Therefore, the development of anti tumor responses can be dramatically influenced not only by costimulation, b ut also by the cytokine and chemokine production of DCs, which must be cons idered in the development of cancer vaccines.