Mechanism of third signals provided by IL-12 and OX-40R ligation in eliciting therapeutic immunity following dendritic-tumor fusion vaccination.
Dendritic-tumor heterokaryons generated by electrofusion are highly immunogenic. In animal studies, a single vaccination was therapeutic for tumors established in the lung, skin, and brain. However, effective therapy required a third signal which could be provided by exogenous IL-12 or the agonistic anti-OX-40R monoclonal antibody (mAb). In this study, we investigated the mechanism and mode of actions of these two seemingly distinct adjuvants. In immunotherapy of the MCA205 sarcoma, administration of the neutralizing anti-IL-12 mAb nearly completely blocked the adjuvant effect of IL-12, but had minimal inhibitory effects on anti-OX-40R mAb. By contrast, in vivo administration of the antagonistic anti-OX-40L mAb inhibited the adjuvant effects of both IL-12 and anti-OX-40R mAb. Thus, a common pathway of endogenous OX-40 interaction is critical for the development of a therapeutic immune response. Analysis of the third signal mechanism revealed that in the absence of an adjuvant, vaccination with fusion hybrids led to IL-10 production without eliciting IFN-gamma secreting cells. The addition of IL-12 to vaccination suppressed IL-10 production and initiated sensitization of specific IFN-gamma secreting cells, resulting in a type 1-like antitumor immunity. These findings underscore the significance of the third signal in the design of dendritic cell-based cancer vaccines.
Kuriyama
Hideyuki
H
Center for Surgery Research, Cleveland Clinic, Cleveland, OH 44195, USA.
Watanabe
Satoshi
S
Kjaergaard
Jorgen
J
Tamai
Hidemasa
H
Zheng
Rongxiu
R
Weinberg
Andrew D
AD
Hu
Hong-Ming
HM
Cohen
Peter A
PA
Plautz
Gregory E
GE
Shu
Suyu
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002459:Cell Fusion; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand / Q000494:pharmacology* / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000628:therapy*; D014611:Vaccination / Q000379:methods
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D053278:OX40 Ligand; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma