Mechanism of third signals provided by IL-12 and OX-40R ligation in eliciting therapeutic immunity following dendritic-tumor fusion vaccination

Kuriyama, Hideyuki; Watanabe, Satoshi; Kjærgaard, Jørgen; Tamai, Hidemasa; Zheng, Rongxiu; Weinberg, Andrew D.; Hu, Hong Ming; Cohen, Peter A.; Plautz, Gregory E.; Shu, Suyu

doi:10.1016/j.cellimm.2006.11.002

Cited by 22 publications

(11 citation statements)

References 47 publications

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“…It was found that for vaccines to be effective against established tumors, an adjuvant was required, such as exogeneously-supplied recombinant IL-12 p70 (Fig. 1B) or agonistic OX-40L mAb (11). This property of adjuvantdependency prompted us to examine the potential of alternative adjuvants for improving antitumor responses.…”

Section: Resultsmentioning

confidence: 99%

“…Although this vaccine modality is exceptional for its capacity to bypass the constraints of exogenous processing to present endogenous tumor proteins in both MHC Class I-and II-restricted, and highly costimulatory contexts, vaccination has consistently benefited from parenteral codelivery of third signals for maximized therapeutic efficacy. Among tested parenteral third signals, IL-12 and OX40 ligating monoclonal antibody (mAb) have proved particularly effective (10,11). Here, we show that fusion hybrid vaccination plus a single TLR agonist induces no detectable therapeutic antitumor immunity, whereas vaccination plus paired TLR agonists show powerful therapeutic responses against established lung metastases derived from the MCA205 sarcoma.…”

Section: Introductionmentioning

confidence: 98%

“…Culture supernatants from 24-h-stimulated DC cultures were subjected to ELISA analysis for IL-12 p70, via OPT-EIA kits (BD/PharMingen) according to manufacturer's recommended protocol. For intracellular fluorescence-activated cell sorting (FACS), lymph node cells harvested 7 d after vaccination were polyclonally expanded with anti-CD3 mAb and IL-2 as described previously (11). Cells were then harvested and cocultured with tumor targets at a 2:1 ratio in the presence of brefeldin A.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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]

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…Snyder et al (73) have also reported that exogenous rIL-12 increases CD40L expression on primary human PBMC cultures resulting in their enhanced activation. It has also been suggested that when used as an adjuvant, IL-12 enhances the OX-40 (CD134) receptor (OX-40R)/OX-40 ligand (OX-40L) interaction, which has been shown to be critical for the generation of a functional antitumor immune response (74). OX-40R (expressed on T cells), when binding to OX-40L (expressed on DCs), was shown to exert significant costimulatory effects on T cell proliferation, survival, and cytokine production (75).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Vaccination with Simian Immunodeficiency Virus (SIV)-DNA+IL-12 or IL-15 Induces Distinct CD8 Memory Subsets in SIV-Infected Macaques

Halwani

Boyer

Yassine‐Diab

et al. 2008

The Journal of Immunology

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DNA vaccination is an invaluable approach for immune therapy in that it lacks vector interference and thus permits repeated vaccination boosts. However, by themselves, DNA-based vaccines are typically poor inducers of Ag-specific immunity in humans and non-human primates. Cytokines, such as IL-12 and IL-15, have been shown to be potent adjuvants for the induction and maintenance of cellular immune responses, in particular during HIV infection. In this study, we examined the ability of therapeutic vaccination with SIV-DNA+IL-12 or IL-15 as molecular adjuvants to improve DNA vaccine potency and to enhance memory immune responses in SIV-infected macaques. Our results demonstrate that incorporating IL-12 into the vaccine induces SIV-specific CD8 effector memory T cell (TEM) functional responses and enhances the capacity of IFN-γ-producing CD8 TEM cells to produce TNF. Lower levels of PD-1 were expressed on T cells acquiring dual function upon vaccination as compared with mono-functional CD8 TEM cells. Finally, a boost with SIV-DNA+IL-15 triggered most T cell memory subsets in macaques primed with either DNA-SIV or placebo but only CD8 TEM in macaques primed with SIV-DNA+IL-12. These results indicate that plasmid IL-12 and IL-15 cytokines represent a significant addition to enhance the ability of therapeutic DNA vaccines to induce better immunity.

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“…2). 61 Importantly, the combination of exogenous rIL-12 and anti-OX40 greatly augmented T cell-mediated anti-tumor immunity in several pre-clinical tumor models, 61,76,77 suggesting a potent synergistic effect between these two molecules.…”

Section: The Effects Of Ox40 Ligation On T Cell Accumulation Andmentioning

confidence: 98%

The Role of OX40-Mediated Co-stimulation in T-Cell Activation and Survival

2009

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The extent of T cell activation, proliferation, and survival that follows T cell receptor ligation is controlled by several factors including the strength of TCR stimulation, the availability of pro-survival cytokines, and the presence or absence of co-stimulatory signals. In addition to engagement of the CD28 co-stimulatory receptor by its natural ligands, B7.1 (CD80) and B7.2 (CD86), recent work has begun to elucidate the mechanisms by which signaling through the OX40 (CD134) co-stimulatory receptor, a member of the TNFR super-family, affects T cell responses. Importantly, OX40 ligation has been shown to augment CD4 and CD8 T cell clonal expansion, effector differentiation, survival, and in some cases, abrogate the suppressive activity of regulatory FoxP3+CD25+CD4+ T cells. In this review, we will focus on the mechanisms regulating OX40 expression on activated T cells as well as the role of OX40-mediated co-stimulation in boosting T cell clonal expansion, effector differentiation, and survival.

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Mechanism of third signals provided by IL-12 and OX-40R ligation in eliciting therapeutic immunity following dendritic-tumor fusion vaccination

Cited by 22 publications

References 47 publications

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

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

Therapeutic Vaccination with Simian Immunodeficiency Virus (SIV)-DNA+IL-12 or IL-15 Induces Distinct CD8 Memory Subsets in SIV-Infected Macaques

The Role of OX40-Mediated Co-stimulation in T-Cell Activation and Survival

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