Abstract
Dendritic cells(DCs) are the most potent antigen presenting cells and DCs play a crucial role in the generation of antitumor immune responses. Using recently developed methods, it is now possible to culture large numbers of DCs from the adherent fraction of peripheral blood mononuclear cells and CD 34+ hematological stem cells. Antigen loading to DC has been demonstrated using a variety of strategies including direct delivery of exogenous peptide fragments or tumor extracts, or by endogenous antigen expression and processing within DCs after delivery of antigen-encoding DNA molecule. DCs efficiently take up soluble and cell-derived protein antigens, but some studies have recently demonstrated that DCs expressing vector encoded tumor associated antigens (TAA) can induce protective and therapeutic immunity in murine cancer models. The transduction of DCs with a TAA-encoding transgene offers several potential advantages over peptide-pulsing. First, expression of an entire TAA gene would enable them to efficiently present multiple epitopes associated with different MHC class I and II molecules. In this way, gene-modified DCs would likely stimulate multiple T-cell clones, each one reactive to a different epitope from the same tumor antigen. And there is no need to carefully identify and synthesize different peptides to be used with every possible MHC subtype. Second, TAA expression within DCs provide the cell with a renewable supply of antigen for presentation, and DCs can present antigen for long time (at least 6 days). Various methods of gene transfer to DCs were examined, including recombinant adenovirus vector, retroviral vectors, DNA/liposome complex and electroporation. Retroviruses have been used to transduce human DCs in vitro. Human DCs progenitors (CD 34+cell) were shown to differentiate into normal DCs after transduction of retroviruses. But the transduction rates were lower than the adenoviral systems. Adenovirus rarely integrates into host genome. It also transfects a large number of terminally differentiated human DCs. For immunotherapy, DCs expressing adenovirus vector encoded TAA are the most attractive candidate. Although some important questions still need to be answered, this approach to immunotherapy of cancer may be promising.
