Abstract
We are developing vaccines that activate tumor-specific CD4+ T cells. The cell-based vaccines consist of MHC class I+ tumor cells that are genetically modified to express syngeneic MHC class II and costimulatory molecules. Previous studies demonstrated that treatment of mice with established tumors with these vaccines resulted in regression of solid tumors, reduction of metastatic disease, and increased survival time. Optimal vaccines will prime naïve T cells and activate T cells to tumor peptides derived from diverse subcellular compartments, since potential tumor antigens may reside in unique cellular locales. To determine if the MHC class II/costimulatory molecule vaccines fulfill these conditions, the vaccines have been tested for their ability to activate antigen-specific, naïve, transgenic CD4+ T lymphocytes. MHC class II(+)CD80+ vaccine cells were transfected with hen eggwhite lysozyme targeted to the cytosol, nuclei, mitochondria, or endoplasmic reticulum, and used as antigen-presenting cells to activate I-Ak-restricted, lysozyme-specific CD4+ 3A9 transgenic T cells. Regardless of the cellular location of lysozyme, the vaccines stimulated release of high levels of IFN-gamma and IL-2. If the vaccines coexpressed the MHC class II accessory molecule invariant chain, then IFN-gamma and IL-2 release was significantly reduced. These studies demonstrate that in the absence of invariant chain the MHC class II and CD80 tumor cell vaccines (1) function as antigen-presenting cells to activate naïve, tumor-specific CD4+ cells to endogenously synthesized tumor antigens; (2) polarize the activated CD4+ T cells toward a type 1 response; and (3) present epitopes derived from varied subcellular locales.