Tumor cells may escape immune surveillance in an immune-competent host because they lack appropriate signals essential for the activation of the host immune system. Anti-tumor immune responses are primarily mediated by T cells. In addition to proper T cell receptor and MHC interactions, optimal activation of T cells also requires the presence of co-stimulatory molecules and adhesion molecules. B7 antigens present on activated B cells are the most well characterized co-stimulatory molecules. Tumor cells may undergo many changes that allow them to escape immune surveillance. They may down regulate the expression of their MHC molecules. They may alter their antigen processing pathways, resulting in their inability to present tumor specific antigens to host T cells. They may lack co-stimulatory antigens or adhesion molecules which are essential for full activation of the host immune system. They may also produce factors which modify host immune responses. Activated B cells are the most effective antigen presenting cells. We therefore hypothesized that fusing a tumor cell with an activated B cell could create a hybridoma that both produced tumor specific antigens and had the necessary machinery for antigen presentation and T cell activation. BERH-2 is a rat hepatocellular carcinoma. BERH-2 cells is tumorigenic and lack MHC class II antigen and the co-stimulatory molecule B7. We fused BERH-2 cells with activated B cells in an attempt to make BERH-2 cells immunogenic. The fused cells (BERH-2-13) express both MHC class II antigen and B7. BERH-2-B cells lost tumorigenicity and became immunogenic. Rats injected with BERH-2-B cells became resistant to challenge with parental BERH-2 cells. Established BERH hepatomas were cured by injection of BER-2-B cells. Both CD4+ and CD8+ cells were essential for the induction of protective immunity. However, only CD8+ cells were required for the eradication of BERH-2 tumors. Immunity elicited with BERH-2-B is tumor specific. We propose to investigate the mechanisms which rendered these hybrid tumor cells immunogenic. We will characterize the antigen specificity's of the T lymphocytes involved in tumor destruction. We will determine whether this approach can be used in other tumors. More importantly, we will determine whether immunization with hybrid tumor cells can affect the de novo progression of tumors. Using hybrid tumor cells to elicit anti-tumor immune responses may provide a new strategy for cancer immunotherapy.
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