Paired Toll-like receptor agonists enhance vaccine therapy through induction of interleukin-12.
Minimal requirements for generating effective immunity include the delivery of antigenic (signal 1) and costimulatory (signal 2) signals to T lymphocytes. Recently, a class of third signals, often delivered by antigen-presenting dendritic cells, has been shown to greatly enhance immune responses, especially against tumors. Among signal 3 factors, interleukin (IL)-12 is particularly effective and can be conditionally induced by agonists of Toll-like transmembrane receptors (TLR). In this study, we assessed the therapeutic effect of adjuvant TLR agonist administration upon the capacity of dendritic cell (DC)-tumor electrofusion hybrids to eradicate established MCA205 sarcomas in syngeneic mice. Paired, but not solitary combinations of polyinosine:polycytadilic acid (P[I:C]; TLR3 agonist) and CpG DNA (ODN1826l; TLR9 agonist) stimulated IL-12 secretion from DCs in vitro and synergized with vaccination to achieve potent tumor rejection. Therapeutic effects, however, required coadministration of paired TLR agonists and DC-tumor fusion hybrids. The administration of TLR agonists alone or with fusion vaccine induced transient splenomegaly but without apparent toxicity. The therapeutic effects of this immunization regimen were significantly abrogated through the neutralization of IL-12p70, indicating that production of this third signal was essential to the observed tumor regression. These results show the profound functional consequences of TLR cooperativity and further highlight the critical role of IL-12 in antitumor immunity.
Center for Surgery Research, Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Rongxiu
R
Zheng
Peter A
PA
Cohen
Christopher A
CA
Paustian
Terrence D
TD
Johnson
Walter T
WT
Lee
Suyu
S
Shu
Gary K
GK
Koski
D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D051193:Toll-Like Receptors / Q000819:agonists*; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology*
D019496:Cancer Vaccines; D051193:Toll-Like Receptors; D014612:Vaccines; D018664:Interleukin-12