NK1.1 Cells Express 4-1BB (CDw137) Costimulatory Molecule and Are Required for Tumor Immunity Elicited by Anti-4-1BB Monoclonal Antibodies

The 4-1BB (CDw137) T-cell molecule is a member of the TNF receptor family and triggering by either 4-1BB ligand or antibody ligation induces T-cell activation and growth. We have recently demonstrated that administration of anti-4-1BB monoclonal antibodies (mAb) induced the regression of established large tumors in several mouse models by activation of T-cell-mediated immunity. Herein we report that selective depletion of natural killer (NK) cells in mice by the anti-AsialoGM1 or anti-NK1.1 antibodies completely abrogated the antitumor effect of anti-4-1BB mAb. However, it is unlikely that NK1.1 cells are the effectors of the response because P815 cells are resistant to lysis by NK1.1 cellsin vitro.Despite the fact that activated NK1.1 cells express 4-1BB on their surface, redirection of NK1.1 cells by anti-4-1BB mAb or by transfection into P815 cells of the 4-1BB natural ligand did not trigger cytolysis. Our results thus gain further insight into the cellular mechanisms of the antitumor effects of anti-4-1BB mAb and implicate an immunoregulatory rather than effector function of 4-1BB molecule on NK1.1 cells.