Paired Toll-like Receptor Agonists Enhance Vaccine Therapy through Induction of Interleukin-12

Abstract

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 IL12p70, 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. [Cancer Res 2008;68(11):4045-9]

Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid–immunoglobulin complexes in humans

“…The vast majority of vaccine studies that incorporate TLR agonists have focused on single TLR adjuvants, while our studies suggest that effective responses commonly utilize multiple TLR-activating pathways with minimal toxicity. The antitumor effectiveness and low toxicity of employing multiple TLR agonists for vaccination has been supported by recent animal studies (53). Our studies further highlight the potential in vivo importance of antigen-specific antibodies in efficiently delivering immunostimulatory nucleic acids to activate TLRs.…”

Ig-Like Transcript 3 Regulates Expression of Proinflammatory Cytokines and Migration of Activated T Cells

“…Attempts to use DC-based vaccines to mount a strong Ag-specific immune response against tumorassociated Ags or pathogenic agents, which elude the human immune system, rely on the use of adjuvants. Various TLR ligands have been used with some success as adjuvants in DCbased vaccines against tumor-associated Ags (35)(36)(37)(38). The present findings offer the tantalizing possibility that knockdown of ILT3 could be used as an adjuvant itself to improve the effectiveness of DC based vaccines to generate immunogenic responses against tumor Ags or chronic pathogenic infections.…”

Xenogeneic immunization with human tyrosine hydroxylase DNA vaccines suppresses growth of established neuroblastoma

“…The crucial importance of mutated ubiquitin in this respect has already been shown in the past and is probably the reason for the induction of a very effective MHC class I antigen epitope presentation after proteasomal degradation in the antigenpresenting cells after oral vaccination with vaccine-carrying attenuated S. typhimurium (20). Besides, it could be shown by others that hypomethylated CpG motives, which are included in our bacterial plasmid DNA, effectively induce IL-12 secretion by dendritic cells (48), thereby providing comparable costimulatory conditions. However, the costimulatory effects of additional cytokine sequences to provoke a Th1-directed immune response should not be underestimated or ignored for the application of DNA vaccines in humans (49).…”