4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner.
4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal. Here we have shown that treatment of tumor-bearing mice with agonistic 4-1BB-specific Abs can lead to T cell-mediated tumor rejection. In vivo mAb depletion experiments demonstrated that this rejection requires CD8(+) cells but not CD4(+) or NK cells. Both IFN-gamma- and CD40-mediated signals were also required, because no benefit was observed on treatment with 4-1BB mAb in mice in which the genes for these molecules had been knocked out. Interestingly, 4-1BB-mediated stimulation of immune responses in CD40L(-/-) mice is effective (although at a reduced level), and may suggest the existence of an alternative ligand for CD40. Additional experiments in IL-15(-/-) mice indicate that IL-15 is not required for either the generation of the primary tumor-specific immune response or the maintenance of the memory immune response. In contrast, the presence of CD4 cells during the primary immune response appears to play a significant role in the maintenance of effective antitumor memory. Finally, in mice in which the number of dendritic cells had been expanded by Fms-like tyrosine kinase3 ligand treatment, the antitumor effects of 4-1BB ligation were enhanced.
Miller
Robert E
RE
Department of Cancer Biology, Immunex Research and Development, Seattle, WA 98101, USA.
Jones
Jon
J
Le
Tiep
T
Whitmore
James
J
Boiani
Norman
N
Gliniak
Brian
B
Lynch
David H
DH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005802:Genes, MHC Class II; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; 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; D015703:Antigens, CD; D019013:CD40 Antigens; D019409:Interleukin-15; D008565:Membrane Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C084881:flt3 ligand protein; D007371:Interferon-gamma