Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response.

CD70 and CD80 are co-stimulatory molecules which belong to the tumor necrosis factor family and the B7 family respectively. When they are co-expressed by gene-modified TS/A tumor cells, they provide an efficient protective and long-lasting T-dependent antitumor response. We first showed that when CD70 and CD80 were delivered in the tumor environment by gene-modified fibroblasts, but were not expressed by the tumor cells themselves, no antitumor response was observed. We next assessed whether the intracytoplasmic domains of CD70 and CD80 contribute to enhance the co-stimulatory activity necessary to induce effective T cell-tumor cell interactions and T cell-dependent antitumor response. TS/A cells were gene-modified to express different combinations of deleted (CD70Delta and CD80Delta) or full-length CD70 and CD80 co-stimulatory molecules. In vitro, the CD80 intracytoplasmic domain was required to regulate CD80 membrane redistribution by interacting with the actin cytoskeleton. The loss of the CD70 intracytoplasmic domain did not alter its ability to relocate on the surface membrane, but failed to co-stimulate T cell proliferation. In vivo experiments in syngeneic BALB/c mice showed that the CD70/CD80-TS/A and the CD70Delta/CD80-TS/A tumors were rejected via CD8 T cells, whereas CD70/CD80Delta-TS/A and CD70Delta/CD80Delta-TS/A tumors were not. The mice that rejected CD70Delta/CD80-TS/A tumors showed decreased protection against injection of parental TS/A cells when compared to mice which rejected CD70/CD80-TS/A tumors. These results showed that the intracytoplasmic domain of CD80 was critical for the effector phase of CD8 T cell-dependent tumor rejection and that the CD70 intracytoplasmic domain could mediate proliferative or surviving signals required for optimal effector/memory CD8 T cell generation.