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 cells in 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.