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.
Melero
I
I
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington, 98121, USA.
Johnston
J V
JV
Shufford
W W
WW
Mittler
R S
RS
Chen
L
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD; D000950:Antigens, Ly; D000954:Antigens, Surface; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009369:Neoplasms / Q000276:immunology; D011506:Proteins / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000950:Antigens, Ly; D000954:Antigens, Surface; C527203:KLRB1 protein, human; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9