CD40 and CD70 Co-Stimulate a Potent In Vivo Antitumor T Cell Response

In several studies, CD80, a potent co-stimulatory molecule, has been reported to be responsible for the induction of CD8+ antitumor T cell responses by CD80-transfected tumor cells. However, expression of CD80 by tumors not always ensures generation of a T cell-mediated antitumor response. Variables such as the inherent immunogenicity of a tumor and its major histocompatibility complex (MHC) expression status affect the efficacy of this approach. Therefore, in this study two other co-stimulatory ligands, CD40 and CD70, have been investigated for their ability to co-stimulate antitumor responses. The efficacy of CD40 and CD70 is compared with that of CD80, with respect to CD4 and CD8 T cell co-stimulatory capacity in vitro and their ability to induce in vivo antitumor responses. Furthermore, CD40 and CD70 are tested for their capacity to induce a long-lived memory response in vivo, as defined both by induction of tumor-specific cytotoxic T lymphocytes (CTLs) and rejection of wild-type tumor cells. It was found that, despite the fact that CD40 predominantly stimulates CD4 T cells, CD40-transfected MHC class II-negative P815 tumor cells become highly immunogenic and induce long-lasting memory tumor-specific CTLs in vivo. Furthermore, CD40 and CD70 emerge as powerful and even superior alternatives to CD80 for improving tumor immunogenicity in vivo. While the mechanisms by which they do so remain to be defined, these findings suggest additional strategies for immunotherapy.