Breaking tolerance to tumors with dendritic cell-based immunotherapy.

ABSTRACT

Dendritic cells (DC) are the most potent antigen-presenting cells known, capable of priming both naïve CD4 and CD8 T lymphocytes. In their immature state DC are especially efficient at ingesting dying cells and processing their antigens while in their mature state DC express high levels of both MHC class I and II antigens as well as a variety of costimulatory molecules needed to induce a primary T cell response. In addition to stimulating adaptive T cell responses, DC can stimulate NK cells and B cells. Their dual role in innate and adaptive immunity led us to explore their potential utility in tumor immunotherapy. The results of clinical trials in which autologous DC loaded with tumor antigen are administered to tumor-bearing patients have been promising, but overall immunologic potency and clinical efficacy have been unsatisfactory. It has become clear that more potent and more efficient DC based immunotherapies are needed, preferably based on in vivo targeting of DC rather than in vitro manipulation followed by systemic administration of the cells. Recent studies in animal models suggest that DC can be loaded with antigen and activated in vivo in a manner that results in potent antitumor immunity. Two approaches to DC targeting are described in this review, both of which have been shown to overcome immune tolerance to tumors and induce dramatic tumor regression.