Utilization of oncoprotein-pulsed dendritic cells as tumor vaccines

Abstract

Dendritic cells (DCs) are the most potent professional antigen-presenting cells with exquisite capacity to interact with T cells and initiate their responses. They specialize in capturing and processing antigens to form MHC peptide complexes (BubenõÂ k 1996). Two key functions of DCs segregate over time. First, the immature DCs, which are found in most of the non-lymphoid and all lymphoid tissues of the body, internalize the antigen. Then, a day or more later, they express the processed antigen in the context of MHC molecules on the cell surface and stimulate T cells. The CD8 + T cells are stimulated in the context of MHC class I molecules, whereas the CD4 + T cells are stimulated in the context of MHC class II molecules (Banchereau and Steinman 1998). Both the CD4 + helper T cells and the CD8 + cytotoxic T lymphocyte precursors must recognize antigen on the same DC (Keene and Forman 1982;Bennett et al. 1997). This ®nding led to the view that help for CD8 + T cell responses is mediated via soluble, shortrange (BubenõÂ k et al. 2000) cytokine signals such as interleukin-2 which are secreted by activated CD4 + T cells. In other words, the DC is required to facilitate delivery of short-range cytokines secreted by the CD4 + helper T cells to the antigen-speci®c CD8 + T cells by bringing the appropriate antigen-speci®c CD4 + and CD8 + T cells together (Clarke 2000). Alternatively, the CD4 + T help is delivered indirectly, through activation and conversion of the DC into a stimulatory cell for CD8 + T lymphocyte priming (Guerder and Matzinger 1992). It has been shown that CD4 + T cell help for CD8 + T cell priming occurs through CD40-CD40L interaction. After recognition of antigen expressed on the surface of DCs, CD40L is rapidly upregulated on CD4 + T cells. Signaling through CD40 on DCs can increase the expression of costimulatory and adhesion molecules such as CD80, CD86, CD23, CD58, and CD54, as well as upregulating class I and class II MHC expression on DCs, which are the events required for cytotoxic T lymphocyte responses (Caux et alMoreover, CD40 signaling may replace the requirement for CD4 + T cell help in cytotoxic T lymphocyte responses. The reports by Bennett et al. (1998) and Schoenberger et al. (1998) indicate that signaling through CD40 on DCs mediated by anti-CD40-stimulating antibody can induce CD8 + T cell priming in the absence of CD4 + T helper cells, thereby weakening the ®rst alternative, i.e., the view that help is delivered through CD4 + T cell-secreted cytokines.The unique antigen-presenting capabilities of DCs make them attractive vehicles for the delivery of therapeutic cancer vaccines. The working hypothesis for utilization of DC-based cancer vaccines is that lack of tumor antigen presentation on mature, stimulatory DCs in vivo, which is a major problem in tumor-bearing individuals, can be bypassed by direct loading of DCs with oncoproteins in vitro, ensuring the transfer of the immunodominant peptides on the adequate antigen-presenting molecules (Schuler and Steinman 1997). Indirect eviden...