A murine model for neuroblastoma, Neuro-2a (N2a), was used to establish a model tumor vaccine. An aggressive subclone of N2a and the less aggressive parental line were transfected with CD80, CD86, or both molecules and stable lines were established. The less aggressive N2a expressing either CD80 or CD86 induced anti-tumor immunity. In contrast, dual expression of CD80 and CD86 was required to initiate a protective anti-tumor immune response against the aggressive subclone. Control of tumor growth was dependent on CD8+ lymphocytes that infiltrated dual-expressing (CD80 and CD86) lesions. These tumor-infiltrating lymphocytes (TIL) exhibited a non-classical mechanism of tumor cell lysis that may require both the up-regulation of cell surface molecules on the tumor and the subsequent lytic activity normally associated with CD8+ TIL. Although Fas was up-regulated by the tumor in the presence of IFN-gamma, N2a and transfected N2a cell lines were not sensitive to Fas-mediated lysis.