| To date, there are few successful cases in the immunotherapy of cancer patients. The reasons for this have been the limited availability of tumor-associated antigens (TAA) and the inability to deliver such antigens in a manner that renders them immunogenic and activates T cell responses in patients with cancer. However, recent insights into the role of dendritic cells (DC) may provide the basis for generating more effective antitumor immune responses. DC are potent professional antigen-presenting cells (APC) with the capacity to capture, process, and present antigen to T cells. They can both elicit primary and boost secondary immune responses. Since their originalidentification by Steinman, much attention is being focused on the role of DC in eliciting antitumor immunity and in the potential therapeutic applications.In recent years, it was found that several cytokines support the in vitro differentiation and maturation of DC derived from bone marrow or blood progenitor cells. CD 14* monocytes or bone marrow derived hematopoietic progenitor cells cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 differentiate into efficient APC with morphology and cell surface molecule expression typical of immature DC. It was demonstrated that a variety of factors (such as LPS, TNF-a, IL-1, monocyte-conditioned medium, and CD40 receptor cross-linking) induce the maturation of immature DC to mature DC that are much more potent in activating T cells by increasing the expression of costimulatory molecules and cytokines, promoting the migration of DC to draining lymph nodes, and down-regulating the capacity of DC to capture and process antigen. At present, in an attempt to stimulate specific antitumor immunity, experimental models and clinical studies are currently evaluating the potent antigen-presenting capacity of DC combined with single or multiple tumor antigen epitopes. However, there are several problems in utilizing pulsing DC with synthetic immunodominant peptides from identified antigens. 1) the potential induction of tolerance; 2) the need to determine the patient's HLA haplotype, the limitation of therapy to patients whose tumors express defined specific tumor antigens in the context of the correct HLA phenotype, the unavailability of peptides for all HLA haplotypes; 3) the lack of CD4 help cell-related epitopes for most antigens; and 4) the CTL resulting from such protocols have a good in vitro capacity to kill peptide-pulsed target cells but only a modest capacity to kill tumor cells. To circumvent these deficits, novel antigen-delivery systems utilizing cytokine gene-modified tumor cells and DC or fusion of DC with tumor cells have resulted in induction of antitumor immunity. However, thisUapproach is difficult in some cases (for example in breast cancer) because only rarely has it been possible to isolate enough viable tumor cells from an individual to prepare the vaccine. It has been reported by Candido et al (2001) that intratumoral delivery of DC could efficiently induce specific antitumor immunity, resulting in tumor growth inhibition in established breast cancer. Unfortunately, tumor cells can secrete immunosuppressor factors (such as IL-10, TGF-P, VEGF) to interfere with DC maturation and function. To overcome tumor-mediated inhibition of DC maturation and function in vivo, immunopotentiating cytokines (such as IL-7, IL-12) were used for gene-modification of DC, which has proven to be an efficient way to treat cancer in animal models.Interferon-gamma (IFN-y) is a product of Thl, cytotoxic T lymphocytes (CTL) and NK cells, and is one of the major effector molecules in cell-mediated immunity. It enhances Thl cell growth, inhibits Th2 cell growth and enhances the cytotoxic activity of CD8+ T cells and NK cells as well as stimulates B cell IgG2a production. IFN-y also leads to an increase in MHC class I and II expression and contributes to efficient antigen presentation to lymphocytes. It has recently been demonstrated that purified mouse DC were also capabl...
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