Anti-CD40 antibody induces antitumor and antimetastatic effects: the role of NK cells.
We assessed the effect of the stimulatory anti-CD40 Ab on NK cell activation in vivo and the therapeutic potential of activated NK cells in tumor-bearing mice. Single-dose i.p. injection of the anti-CD40 Ab resulted in production of IL-12 and IFN-gamma in vivo, followed by a dramatic increase in NK cell cytolytic activity in PBLs. NK cell activation by anti-CD40 Ab was also observed in CD40 ligand knockout mice. Because NK cells express CD40 ligand but not CD40, our results suggest that NK activation is mediated by increased cytokine production upon CD40 ligation of APCs. Treatment of tumor-bearing mice with anti-CD40 Ab resulted in substantial antitumor and antimetastatic effects in three tumor models. Depletion of NK cells with anti-asialo GM1 Ab reduced or abrogated the observed antitumor effects in all the tested models. These results indicate that a stimulatory CD40 Ab indirectly activates NK cells, which can produce significant antitumor and antimetastatic effects.
Turner
J G
JG
Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Rakhmilevich
A L
AL
Burdelya
L
L
Neal
Z
Z
Imboden
M
M
Sondel
P M
PM
Yu
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000517:prevention & control; D005260:Female; D007274:Injections, Intraperitoneal; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000517:prevention & control*; D009447:Neuroblastoma / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D023201:CD40 Ligand