DEVELOPMENT OF IMMUNOGENIC BREAST AND OVA RIAN TUMOR-CELLS FOR VACCINATION

Improved Immunogenicity and induction of Cytolytic T-Lymphocytes after CD80-Transfection: Introduction: There is increasing evidence that tu mours possess potentially recognizable antigens in association with MH C molecules. A possible explanation for the failure of tumour cells to elicit an immune response is their inability to provide costimulatory signals to T-lymphocytes. Presentation of tumour antigens in the abse nce of costimulatory molecules is believed to prevent T cell activatio n but rather induces a state of tolerance towards the tumour. The loss of the MHC and defects in processing and transport mechanisms needed for antigen presentation can contribute to the escape from immunologic al control. Methods and Results: Human tumour cell lines derived from breast and ovarian carcinomas were found to be ineffective in stimulat ing the induction phase of an immune response such as T cell prolifera tion in allogeneic mixed tumour cell lymphocyte cultures. In order to reconstitute the potential to induce primary T cell activation we tran sfected CD80 into a breast (KS) and an ovarian carcinoma (CC) cell lin e. CD80 expression in KS cells resulted in improved primary T cell act ivation whereas it was ineffective in the case of GG cells. However, t reatment of CD80-transfected GG cells with INF-gamma rendered them imm unogenic and resulted in T cell proliferation. Likewise, TNF-alpha and /or INF-gamma augmented T cell proliferation induced by CD80-transfect ed KS cells. Furthermore, T lymphocytes stimulated with cytokine treat ed CD80+ KS cells gave rise to a long-term proliferating CD80+ CTL lin e with class I MHC-restricted cytolytic anti-tumour activity. Discussi on: These studies emphasise the requirement for costimulation in gener ating tumour-specific immunity and demonstrate the efficacy of CD80 in generating CD8+ cytolytic T lymphocytes. The finding that T cells exp anded in this study were class I MHC-restricted and cytolytic suggests that CD80-transfected immunogenic tumour cell variants possess the po tential to activate T cells directed at intracellular tumour antigens. This may also be possible when lymphocytes and tumour cells are allog enic but share a common HLA allele. The data suggest that induction of costimulation by the CD80/CD28 interaction, together with cytokine tr eatment of tumour cells, may lead to effective antitumour immunotherap ies.