ELICITATION OF A SYSTEMIC AND PROTECTIVE ANTIMELANOMA IMMUNE-RESPONSEBY AN IL-2-BASED VACCINE - ASSESSMENT OF CRITICAL CELLULAR AND MOLECULAR-PARAMETERS

We have established a model for the immunologic rejection of melanoma cells. Using a receptor-mediated, adenovirus-augmented gene delivery s ystem (transferrinfection) we have shown that, upon transfection with an IL-2 gene construct, MHC class I+/class II- murine M-3 cells lose t heir tumorigenicity in both athymic and euthymic mice. More importantl y, we found that these melanoma cells, which produce high levels of IL -2, can be used to induce a long-lasting anti-tumor immune response in syngeneic euthymic DBA/2 mice but not in athymic animals. This immune response, which can also be elicited by coadministration of nonmodifi ed, irradiated M-3 cells and IL-2-transduced fibroblasts, results in t he rejection of a subsequent challenge with M-3 cells or, in the elimi nation of preexisting M-3 cancer cell deposits. We found that transfer of T cell-enriched, but not of T cell-depleted, splenocytes from immu nized mice conferred protection against M-3 cells, but not against unr elated KLN 205 cancer cells. Transfer of either CD4(+) or CD8(+) T cel ls led to only partial protection against challenge with wild-type M-3 cells. Our further observations that T cell-enriched, but not T cell- depleted splenocytes of immunized animals are capable of tumor-specifi c lytic activity and that this activity resides in the CD8(+) cell pop ulation are compatible with the assumption that MHC class I-restricted T cell cytotoxicity is a biologically relevant effector mechanism in this model. That other mechanisms also contribute to melanoma cell des truction is evidenced by the presence of large numbers of macrophages and granulocytes in addition to T cells at the challenge sites of immu nized mice.