Dendritic cells transfected with interleukin-12 and tumor-associated antigen messenger RNA induce high avidity cytotoxic T cells

Bontkes, Hetty J.; Kramer, Debbie; Ruizendaal, Janneke J.; Kueter, Esther W. M.; Tendeloo, Viggo Van; Meijer, Chris J.L.M.; Hooijberg, Erik

doi:10.1038/sj.gt.3302874

Cited by 72 publications

(65 citation statements)

References 42 publications

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“…Indeed, although no differences were observed in the cytokine expression profile of IDC and LC primed T cells, transduction with IL-12p70 significantly improved the priming efficiency of both IDC and LC and abrogated the difference in tumor-specific CD8 ϩ priming efficiency between the DC subsets. Moreover, introducing IL-12p70 also resulted in a more advanced effector T cell differentiation with enhanced functional avidity and tumor cell recognition abilities of the IDC-and LC-generated CD8 ϩ T cells, as we also recently described using mRNA-transfected MoDC (39).…”

Section: Discussionmentioning

confidence: 55%

Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model

Santegoets

Bontkes²,

Stam³

et al. 2008

The Journal of Immunology

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Dendritic cells (DC) are increasingly applied as a cellular adjuvant in immunotherapy of cancer. Two major myeloid DC subsets are recognized: interstitial DC (IDC) that infiltrate connective tissues and Langerhans cells (LC) that line epithelial surfaces. Yet, functional differences between IDC and LC remain to be defined. We recently showed that the CD34+ acute myeloid leukemia cell line MUTZ-3 supports differentiation of both DC-SIGN+ IDC and Langerin-positive Birbeck granule-expressing LC. By comparative functional characterization of MUTZ-3 IDC and MUTZ-3 LC, we aimed to elucidate the relative abilities of these two DC subsets to induce a specific T cell response and reveal the more suitable candidate for use as a clinical vehicle of tumor vaccines. Although mature LC and IDC displayed comparable lymph node-homing potential, mature LC showed higher allogeneic T cell stimulatory capacity. Nevertheless, IDC supported the induction of tumor Ag-specific CD8+ T cells at an overall higher efficiency. This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15. Although this inability did not result in a detectable deviation in the cytokine expression profile of primed T cells, transduction with IL-12p70 significantly improved priming efficiency of LC, and ensured a functional equivalence with IDC in this regard. In conclusion, except for the inability of LC to release distinct type 1 T cell stimulatory cytokines, in vitro function of LC and IDC suggests comparable abilities of both subsets for the in vivo induction of antitumor T cells.

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Section: Discussionmentioning

confidence: 55%

Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model

Santegoets

Bontkes²,

Stam³

et al. 2008

The Journal of Immunology

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“…Ϫ effector CTL population was generated (37), in stark contrast to the REHA CTL reported in this study using PME-CD40L DC. Therefore, PME-CD40L DC provide additional costimulation signal(s) in addition to, but dependent on, IL-12 secretion.…”

Section: Cd28mentioning

confidence: 80%

“…In addition, they also display the qualities of terminally differentiated effector cells by expressing IFN-␥ and granzyme B and possessing cytolytic activity. Phenotypically, these effector/memory CTL maintain the expression of both CD27 and CD28 but are CD45RA and CCR7 negative, unlike CTL induced with DC electroporated with IL-12 encoding RNA (37). We have termed this novel subset of T cells: CD28 ϩ rapidly expanding high-avidity (REHA) CTL.…”

mentioning

confidence: 99%

Priming of a Novel Subset of CD28+ Rapidly Expanding High-Avidity Effector Memory CTL by Post Maturation Electroporation-CD40L Dendritic Cells Is IL-12 Dependent

DeBenedette

Calderhead

Ketteringham

et al. 2008

The Journal of Immunology

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Dendritic cell (DC)-based immunotherapeutics must induce robust CTL capable of killing tumor or virally infected cells in vivo. In this study, we show that RNA electroporated post maturation and coelectroporated with CD40L mRNA (post maturation electroporation (PME)-CD40L DC) generate high-avidity CTL in vitro that lyse naturally processed and presented tumor Ag. Unlike cytokine mixture-matured DC which induce predominantly nonproliferative effector memory CD45RA+ CTL, PME-CD40L DC prime a novel subset of Ag-specific CTL that can be expanded to large numbers upon sequential DC stimulation in vitro. We have defined these cells as rapidly expanding high-avidity (REHA) CTL based on: 1) the maintenance of CD28 expression, 2) production of high levels of IFN-γ and IL-2 in response to Ag, and 3) the demonstration of high-avidity TCR that exhibit strong cytolytic activity toward limiting amounts of native Ag. We demonstrate that induction of REHA CTL is dependent at least in part on the production of IL-12. Interestingly, neutralization of IL-12 did not effect cytolytic activity of REHA CTL when Ag is not limiting, but did result in lower TCR avidity of Ag-reactive CTL. These results suggest that PME-CD40L DC are uniquely capable of delivering the complex array of signals needed to generate stable CD28+ REHA CTL, which if generated in vivo may have significant clinical benefit for the treatment of infectious disease and cancer.

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“…Third, data from the literature suggest that TriMix DCs in general and TriMix DCs coelectroporated with TAA mRNA in particular will induce T cells with a higher TCR avidity. Indeed, it has been shown that functional avidity is dependent on IL-12p70 (22) and that DCs coelectroporated with IL-12 mRNA induce T cells with an enhanced functional avidity (23). Because TriMix DCs secrete more IL-12p70 than do classic DCs, it is conceivable that they will also induce T cells with a higher TCR avidity.…”

Section: Resultsmentioning

confidence: 99%

Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients

Bonehill

Nuffel

Corthals

et al. 2009

Clinical Cancer Research

147

119

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Purpose: A critical factor determining the effectiveness of currently used dendritic cell (DC)-based vaccines is the DC activation or maturation status. We have recently shown that the T-cell stimulatory capacity of DCs pulsed with tumor-antigen-derived peptides can be considerably increased by activating the DCs through electroporation with mRNA encoding CD40 ligand, CD70, and a constitutively active Toll-like receptor 4 (TriMix DCs). Here, we investigate whether TriMix DCs can be coelectroporated with whole tumor-antigen-encoding mRNA. Experimental Design: The T-cell stimulatory capacity of TriMix DCs pulsed with the immunodominant MelanA-A2 peptide and that of TriMix DCs coelectroporated with MelanA mRNA were compared in vitro. TriMix DCs were also coelectroporated with mRNA encoding Mage-A3, Mage-C2, tyrosinase, or gp100. The capacity of these DCs to stimulate tumor-antigen-specific T cells in melanoma patients was investigated both in vitro before vaccination and after DC vaccination. Results: Like peptide-pulsed TriMix DCs, TriMix DCs coelectroporated with MelanA mRNA are very potent in inducing MelanA-specific CD8 + T cells in vitro. These T cells have an activated phenotype, show cytolytic capacity, and produce inflammatory cytokines in response to specific stimulation. TriMix DCs coelectroporated with tyrosinase are able to stimulate tyrosinase-specific CD8 + T cells in vitro from the blood of nonvaccinated melanoma patients. Furthermore, TriMix DCs coelectroporated with Mage-A3, Mage-C2, or tyrosinase are able to induce antigen-specific CD8 + T cells through therapeutic DC vaccination. Conclusions: TriMix DCs coelectroporated with whole tumor-antigen mRNA stimulate antigen-specific T cells in vitro and induce antigen-specific T-cell responses in melanoma patients through vaccination. Therefore, they represent a promising new approach for antitumor immunotherapy.The past five decades have witnessed a steady increase in the incidence of malignant melanoma. Whereas early detection and appropriate surgery have improved outcomes, at least one third of patients with early-stage melanoma will develop metastases. The prognosis for patients with malignant metastatic melanoma remains poor. These patients have a median survival of approximately 6 to 8 months, and <5% will generally survive for 5 years or more (1). There is universal agreement that further research to address this problem is critically warranted.Many strategies to enhance specific or nonspecific immunity in melanoma patients have been explored in clinical studies (2). Although the field is relatively new and many clinical variables remain to be investigated, vaccination with tumor-associated antigen (TAA)-expressing dendritic cells (DC) might provide a therapeutic benefit (3). Roughly, the DC life cycle can be divided into two stages: the immature and the mature stage. Immature DCs reside in the periphery and are specialized

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Dendritic cells transfected with interleukin-12 and tumor-associated antigen messenger RNA induce high avidity cytotoxic T cells

Cited by 72 publications

References 42 publications

Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model

Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model

Priming of a Novel Subset of CD28+ Rapidly Expanding High-Avidity Effector Memory CTL by Post Maturation Electroporation-CD40L Dendritic Cells Is IL-12 Dependent

Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients

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