CD40 AND CD70 CO-STIMULATE A POTENT IN-VIVO ANTITUMOR T-CELL RESPONSE

In several studies, CD80, a potent co-stimulatory molecule, has been r eported to be responsible for the induction of CD8(+) antitumor T cell responses by CD80-transfected tumor cells. However, expression of CD8 0 by tumors not always ensures generation of a T cell-mediated antitum or response. Variables such as the inherent immunogenicity of a tumor and its major histocompatibility complex (MHC) expression status affec t 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 c apacity to induce a long-lived memory response in vivo, as defined bot h by induction of tumor-specific cytotoxic T lymphocytes (CTLs) and re jection of wild-type tumor cells. It was found that, despite the fact that CD40 predominantly stimulates CD4 T cells, CD40-transfected MHC c lass II-negative P815 tumor cells become highly immunogenic and induce long-lasting memory tumor-specific CTLs in vivo. Furthermore, CD40 an d CD70 emerge as powerful and even superior alternatives to CD80 for i mproving tumor immunogenicity in vivo. While the mechanisms by which t hey do so remain to be defined, these findings suggest additional stra tegies for immunotherapy.