Tumor associated antigen and interleukin-12 mRNA transfected dendritic cells enhance effector function of natural killer cells and antigen specific T-cells

Bontkes, Hetty J.; Kramer, Duco; Ruizendaal, Janneke J.; Meijer, Chris J.L.M.; Hooijberg, Erik

doi:10.1016/j.clim.2008.02.001

Cited by 51 publications

(39 citation statements)

References 33 publications

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“…It may act together with CD40 signaling provided by helper cells present in the cocultures to enhance IL-12 production by MoDC, which is an essential third signal for the development of CTL responses. However, as we have previously demonstrated for help provided by irradiated PBL (35) or isolated NK cells (46), CTL expansion is even further enhanced by iNKT cells (Fig. 5b) when DC overexpress IL-12.…”

Section: Discussionsupporting

confidence: 73%

IFN-γ-Producing Human Invariant NKT Cells Promote Tumor-Associated Antigen-Specific Cytotoxic T Cell Responses

Moreno

Molling

Mensdorff‐Pouilly³

et al. 2008

The Journal of Immunology

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CD1d-restricted invariant NKT (iNKT) cells can enhance immunity to cancer or prevent autoimmunity, depending on the cytokine profile secreted. Antitumor effects of the iNKT cell ligand α-galactosylceramide (αGC) and iNKT cell adoptive transfer have been demonstrated in various tumor models. Together with reduced numbers of iNKT cells in cancer patients, which have been linked to poor clinical outcome, these data suggest that cancer patients may benefit from therapy aiming at iNKT cell proliferation and activation. Herein we present results of investigations on the effects of human iNKT cells on Ag-specific CTL responses. iNKT cells were expanded using αGC-pulsed allogeneic DC derived from the acute myeloid leukemia cell line MUTZ-3, transduced with CD1d to enhance iNKT cell stimulation, and with IL-12 to stimulate type 1 cytokine production. Enhanced activation and increased IFN-γ production was observed in iNKT cells, irrespective of CD4 expression, upon stimulation with IL-12-overexpressing dendritic cells. IL-12-stimulated iNKT cells strongly enhanced the MART-1 (melanoma Ag recognized by T cell 1)-specific CD8+ CTL response, which was dependent on iNKT cell-derived IFN-γ. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as αGC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN-γ-producing iNKT cells, which may be more effective against tumors in vivo. Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with αGC.

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Section: Discussionsupporting

confidence: 73%

IFN-γ-Producing Human Invariant NKT Cells Promote Tumor-Associated Antigen-Specific Cytotoxic T Cell Responses

Moreno

Molling

Mensdorff‐Pouilly³

et al. 2008

The Journal of Immunology

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“…Two strategies have been reported to augment cytokine secretion by DC, that is, modification of DCs with (1) genes encoding one or multiple cytokines and (2) genes encoding a domain of the transcription factor NF-kB (Lee et al, 2002), resulting in enhanced secretion of multiple proinflammatory cytokines. The impact of cytokines on the induction of antitumor T cell responses has been tested in human and mouse models for interleukin (IL)-12 (helper T type 1 [Th1]-skewing, important for antitumor immune responses) (Nishioka et al, 1999;Ribas et al, 2001Ribas et al, , 2002Vujanovic et al, 2006;Bontkes et al, 2007Bontkes et al, , 2008Tsai et al, 2009), IL-18 (Th1-skewing cytokine) (Tatsumi et al, 2002;Vujanovic et al, 2006;Tong et al, 2008), interferon (IFN)-g (Th1-skewing cytokine) (Xue et al, 2007), IL-2 (T cell proliferation factor) (Ribas et al, 2001), IL-7 (for generation and maintenance of memory T cells) (Westermann et al, 1998;Miller et al, 2000;Ribas et al, 2001;Sharma et al, 2003), tumor necrosis factor (TNF)-a (proinflammatory cytokine and maturation factor for DCs) (Chen et al, 2002;Ye et al, 2006), IFN-a (stimulation of cross-presentation and antitumor immune response) (Tuting et al, 1998), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (DC growth and differentiation factor) (Cao et al, 1998;Ojima et al, 2006). Although most studies stated that the produced cytokines positively influenced the induction of an antitumor immune response, there was also a report on an IL-12-induced dose-dependent inhibition of the antitumor response by a yet undefined mechanism in a mouse melanoma model (Ribas et al, 2002).…”

Section: Cytokines and Chemokines: Signalmentioning

confidence: 99%

Dendritic Cell-Based Cancer Gene Therapy

Smits

Anguille²,

Cools³

et al. 2009

Human Gene Therapy

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In view of their potent antigen-presenting capacity and ability to induce effective immune responses, dendritic cells (DCs) have become an attractive target for therapeutic manipulation of the immune system. The application of tumor-associated antigen (TAA)-expressing DCs for cancer therapy has been the subject of intensive translational investigation. Previous clinical trials demonstrated tumor-specific immune responses without any significant toxicity. However, the clinical success has been modest, because only a limited number of immunized patients demonstrated cancer regression. Considerable progress has been made in the knowledge of DC biology, which opens new avenues for the development of optimized clinical protocols. One such promising approach that might carve its place in the future of DC-based therapy is the use of gene-modified DCs. DCs engineered to express TAAs allow multiepitope presentation by both major histocompatibility complex (MHC) class I and II molecules of full-length TAAs independent of the patient's HLA constitution, as opposed to peptide vaccination strategies. Besides transgene TAA expression, DCs can be genetically modified (1) to express a variety of immune-potentiating molecules (e.g., costimulatory molecules, cytokines, and chemokines) or (2) to downregulate negative modulators of DC functioning, all allowing an enhancement of their immunogenic potential. In the present review, gene delivery systems for DCs are discussed, as well as the various transgenes used for genetic modification of DCs. Moreover, a detailed review of the already published trials using gene-modified DCs is presented and future DC-based strategies targeting multiple layers of the complex cellular immune response are highlighted.

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“…RNA electroporation of MoDCs or B cells with a viral TAP inhibitor is feasible in clinical settings. RNA electroporation has the advantage that the nucleotides are not integrated in the host genome, like viral vectors (33,(49)(50)(51)(52)(53). In our mouse model, TAP-deficient DCs were able to prevent the outgrowth of TAPdeficient tumors (30).…”

Section: Discussionmentioning

confidence: 82%

CD8+ T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population

Lampen¹,

Verweij

Querido³

et al. 2010

The Journal of Immunology

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Tumor associated antigen and interleukin-12 mRNA transfected dendritic cells enhance effector function of natural killer cells and antigen specific T-cells

Cited by 51 publications

References 33 publications

IFN-γ-Producing Human Invariant NKT Cells Promote Tumor-Associated Antigen-Specific Cytotoxic T Cell Responses

IFN-γ-Producing Human Invariant NKT Cells Promote Tumor-Associated Antigen-Specific Cytotoxic T Cell Responses

Dendritic Cell-Based Cancer Gene Therapy

CD8+ T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population

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