Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway.
We have explored the role of an activation-induced T cell molecule, 4-1BB (CDw137), in the amplification of tumor immunity by retrovirus-mediated transduction of the 4-1BB ligand (4-1BBL) into tumor cells. Mice inoculated with P815 tumor cells expressing 4-1BBL developed a strong cytotoxic T lymphocyte (CTL) response and long-term immunity against wild-type tumor. The optimal effect of 4-1BBL in CTL stimulation required B7-CD28 interaction since blockade of this interaction by antibodies down-regulated the expression of 4-1BB on T cells and decreased CTL activity. Furthermore, co-expression of 4-1BBL and B7-1 in the poorly immunogenic AG104A sarcoma enhanced the induction of effector CTL and the rejection of the wild-type tumor while neither 4-1BBL nor B7-1 single transfectants were effective, suggesting a synergistic effect between the 4-1BB and the CD28 co-stimulatory pathways. Our results underscore the importance of the 4-1BB T cell stimulation pathway in the amplification of an antitumor immune response.
Melero
I
I
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, USA.
Bach
N
N
Hellström
K E
KE
Aruffo
A
A
Mittler
R S
RS
Chen
L
L
D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm / Q000276:immunology*; D018106:CD28 Antigens / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018014:Gene Transfer Techniques; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000008:administration & dosage* / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage* / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9