Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.

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Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIVactivated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype.

The use of dendritic cells (DCs) for tumor immunotherapy represents a powerful approach for harnessing the patient's own immune system to eliminate tumor cells. However, suboptimal conditions for generating potent immunostimulatory DCs, as well as the induction of tolerance and suppression mediated by the tumors and its microenvironment have contributed to limited success. Combining DC vaccines with new approaches that enhance immunogenicity and overcome the regulatory mechanisms underlying peripheral tolerance may be the key to achieving effective and durable anti-tumor immune responses that translate to better clinical outcomes. Keywords dendritic cell; tumor immunotherapy; vaccinationDendritic cells (DCs) are the most potent antigen-presenting cells (APCs), capable of activating both naive and memory immune responses, and maintaining the delicate balance between immunity and tolerance. Several studies have demonstrated that antigens expressed by tumors, including tumor-specific antigens, can be loaded on DCs to trigger an immune response in vitro. Clinical trials of antigen-pulsed DCs have been conducted in patients with various types of tumors, including breast cancer, multiple myeloma, prostate cancer, renal cell carcinoma, malignant melanoma, colorectal cancer and non-small-cell lung cancer [201]. While these studies have demonstrated that antigen-loaded DC vaccines are a safe and promising therapy for tumors, their clinical efficacy remains to be established. The first part of this review discusses human DC biology and the second part focuses on the application of DCs for harnessing for anti-tumor immunity. DC biologyThe combined action of both the innate and adaptive immune system is required for the development of protective immune responses. The innate immune response serves as the initial defense against pathogenic organisms or neoplastic cell growth by providing a local and