Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines.
In weakly and poorly immunogenic tumor models, we examined the effects of stimulating CD137 (4-1BB) in vivo by administering anti-CD137 monoclonal antibody after tumor lysate-pulsed dendritic cell (TP-DC) vaccination. TP-DC subcutaneous vaccination induced a transient up-regulation of CD137 on T cells and natural killer (NK) cells within vaccine-primed lymph nodes (VPLNs). In established pulmonary and subcutaneous tumor models, anti-CD137 synergistically enhanced tumor regression after TP-DC vaccination. In the subcutaneous tumor model, the combined therapy resulted in improved survival. Combined therapy also resulted in improved local control of subcutaneous tumor after surgical resection. Anti-CD137 polarized the cytokine release of VPLNs and spleen cells in response to tumor antigen toward a type 1 (interferon-gamma) versus a type 2 (interleukin-4) profile. Cell depletion and the use of knockout animals identified that CD8(+), CD4(+), and NK cells were involved in the tumor rejection response and that CD8(+) cells had the major effector role. Anti-CD137 administration resulted in increased proliferation of adoptively transferred OT-1 CD8(+) T cells in the VPLNs of mice inoculated with B16-OVA TP-DCs. Polarization toward type 1 (interferon-gamma) versus type 2 (interleukin-4) was also observed with the OT-1 cells from VPLNs and spleen cells after anti-CD137 injections. This polarization effect was abrogated by the in vivo depletion of NK cells. These findings indicate that the adjuvant effect of anti-CD137 given in conjunction with TP-DC vaccination is associated with the polarization of T effector cells toward a type 1 response to tumor antigen and is mediated via NK cells.
Ito
Fumito
F
Division of Surgical Oncology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Li
Qiao
Q
Shreiner
Andrew B
AB
Okuyama
Ryuji
R
Jure-Kunkel
Maria N
MN
Teitz-Tennenbaum
Seagal
S
Chang
Alfred E
AE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019496:Cancer Vaccines; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9