Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

Vujanović, Lazar; Szymkowski, David E.; Alber, Sean; Watkins, Simon C.; Vujanović, Nikola L.; Butterfield, Lisa H.

doi:10.1182/blood-2009-08-240325

Cited by 60 publications

(94 citation statements)

References 50 publications

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“…IL-15Ra chaperones IL-15 and mediates its presentation on the surface of DCs (27), thus, DC:NK interactions mediated by IL-15 require cell-to-cell contact. Our observation is in agreement with recent findings by Vujanovic and colleagues, who report that membranebound IL-15 and TNF-a mediate activation between adenovirus-infected DCs and NK cells (48). IL-15 is critical for clearance of several virus infections, including HSV (49) and MCMV (46).…”

Section: Discussionsupporting

confidence: 93%

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IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells

et al. 2011

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There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-DM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV-DM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumorbearing hosts. VSV-DM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV-DM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15-mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies. Cancer Res; 71(7); 2497-506. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 93%

“…IL-15 signaling is important for NK cell development (44,45), and potently activates NK cells for IFN-g production and cytotoxicity (46)(47)(48). IL-15Ra chaperones IL-15 and mediates its presentation on the surface of DCs (27), thus, DC:NK interactions mediated by IL-15 require cell-to-cell contact.…”

Section: Discussionmentioning

confidence: 99%

IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells

et al. 2011

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“…Type-1 polarizing mature dendritic cells (mDC), which we have previously shown to be potent mediators of both adaptive and innate Type-1 immunities, [42][43][44] could be a potent immunization platform for enhancing cross-reactive immunity and treating patients harboring MAGE-A6 C malignancies. Given the link between clinical Mycoplasma infections and pulmonary disease, 34 and taken together with circumstantial reports of spontaneous cancer regression in patients (particularly of hematologic malignancies) recovering from pneumonia, 45,46 it is tempting to consider the possible involvement of exploiting cross-reactive immunity in these complex biological processes.…”

Section: Discussionmentioning

confidence: 99%

“…iDC were generated from the remaining monocytes as previously described. 43 On day 5 of culture, iDC were pulsed with test peptides for 2 h at 37 C, after which 1000 U/mL IFNg and 250 ng/mL lipopolysaccharide (LPS;Sigma-Aldrich) were added directly to culture to mature DCs. After an overnight incubation at 37 C, peptide-pulsed mature DC (mDC) were harvested and used for in vitro stimulation (IVS) experiments.…”

Section: Isolation Of Patient and Healthy Donor Peripheral Blood Monomentioning

confidence: 99%

Molecular mimicry of MAGE-A6 andMycoplasma penetransHF-2 epitopes in the induction of antitumor CD8⁺T-cell responses

et al. 2014

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A promising vaccine strategy for the treatment of cancer involves the use of vaccines incorporating tumor antigenderived synthetic peptides that can be coordinately recognized by specific CD4C and CD8 C T-cells. Previously, we reported that a MAGE-A6-derived peptide (MAGE-A6 172-187 ) and its highly-immunogenic and cross-reactive homolog derived from Mycoplasma penetrans HF-2 permease (HF-2 216-229 ) are promiscuously presented by multiple HLA-DR alleles to responder CD4 C T-cells obtained from healthy donors and melanoma patients. Here, we investigated whether these same peptides could concomitantly stimulate cross-reactive MAGE-A6-specific CD8C T-cell responses in vitro using cells isolated from HLA-A*0201 (HLA-A2)C healthy individuals and patients with melanoma. We now show that MAGE-A6 172-187 and, even more so, HF-2 216-229 , induce memory CD8 C T cells that recognize HLA-A2 C MAGE-A6 C tumor target cells. The immunogenicity of these peptides was at least partially attributed to their embedded MAGE-A6 176-185 and HF-2 220-229 "homologous" sequences. The functional avidity of HF-2 216-229 peptide-primed CD8 C T cells for the MAGE-A6 172-187 peptide was more than 100-fold greater than that of CD8 C T cells primed with the corresponding MAGE-A6 peptide. Additionally, these 2 peptides were recognized in interferon g (IFNg) and granzyme B ELISPOT assays by CD8C T-cell clones displaying variable T-cell receptor (TCR) Vb usage. These data suggest that the immune crossreactivity of the MAGE-A6 172-187 and HF-2 216-229 peptides extends to CD8 C T cells, at least in HLA-A2 C donors, and supports the potential translational utility of these epitopes in clinical vaccine formulations and for immunomonitoring of cancer patients.

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“…For example, the use of apoptotic tumor cellloaded DCs was demonstrated to induce an NK celldependent T cell response [126,127]. Considering the mode of delivery, Vujanovic and colleagues [124] demonstrated, in a recent human trial, that adenoviral transduction, like TLR4 ligand/IFN-␥ maturation, increased the expression of transmembrane TNF and IL-15 on DCs, resulting in enhanced NK cell activation, IFN-␥ secretion, proliferation, and antitumor activities [93,124]. They showed, in vitro, that adenovirustransduced DCs, as compared with protein-or peptide-loaded DCs, are the most successful at inducing NK cell activation [94].…”

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confidence: 99%

NK Cells: Key to Success of DC-Based Cancer Vaccines?

et al. 2012

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After completing this course, the reader will be able to:1. Describe the current in vivo experimental and clinical dendritic cell (DC) vaccination studies encompassing the monitoring of natural killer (NK) cells.2. Discuss the evaluation of NK cell stimulating potency in the design of DC-based cancer vaccines in the preclinical phase and in clinical trials. Explain the added value of immune monitoring of NK cells in cancer vaccination trials.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT NATURAL KILLER CELLS IN CANCERIn the early 1980s, the role of natural killer (NK) cells in defense against cancer was described in seminal reviews [1,2]. A myriad of reports rapidly followed, supporting the involvement and therapeutic potential of NK cells in cancer immunity [3,4]. A range of solid tumors [5][6][7][8][9][10][11][12] and hematological malignancies [13][14][15][16][17][18][19] were shown to be associated with significantly impaired NK cell functions. Importantly, NK cell abnormalities have been shown to be, at least in part, responsible for the failure of antitumor immunity. Deficiencies can reside in all NK cell populations, located in peripheral blood, in (lymphoid) organs, and in the tumor itself [16]. Functional impairment can originate from (a) primary NK cell dysfunction (e.g., imbalanced NK cell receptor expression, impaired cytolytic capacity, reduced cytokine secretion potency), (b) insufficient interaction with other immune cells (e.g., impaired killing of dendritic cells [DCs]) [14], (c) active immune suppression (e.g., regulatory T cell [Treg]-mediated suppression) [20,21], and (d) NK cell resistance mechanisms by tumor cells (e.g., shedding of decoy molecules for activating receptors) [22]. In this regard, multiple cancer studies point toward a prognostic value for NK cells. Table 1 summarizes valuable NK cell parameters used for prognosis of disease progression and patient survival as well as for prediction of therapy efficacy.In humans, NK cells are characterized by a CD56 ϩ CD3 Ϫ NKp46 ϩ phenotype. Based on their CD56 cell-surface density, they can be divided into two subsets with distinct phenotypic properties and key effector functions [23]. The majority (ϳ90%) of peripheral blood NK cells have a CD56 dim CD16 bright phenotype and were originally regarded as the more naturally cytotoxic subset, characterized by high cytotoxic granule and perforin expression and lower cytokine-secreting capacity. The smaller CD56 bright CD16dim/Ϫ NK cell fraction (ϳ10%) constitutively expresses a higher number of cytokine and chemokine receptors and a lower amount of cytotoxic granules, generally showing a poorer cytotoxic capacity but a superior ability to produce abundant immunoregulatory cytokines following activation, in particular the prototypic cytokine interferon (IFN)-␥. Remarkably, these seemingly subtype-specific effector functions appear to be not as restricted as previously thought. Several research groups recently demonstrated that CD56 d...

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Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

Cited by 60 publications

References 50 publications

IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells

IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells

Molecular mimicry of MAGE-A6 andMycoplasma penetransHF-2 epitopes in the induction of antitumor CD8⁺T-cell responses

NK Cells: Key to Success of DC-Based Cancer Vaccines?

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Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

Cited by 60 publications

References 50 publications

IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells

IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells

Molecular mimicry of MAGE-A6 andMycoplasma penetransHF-2 epitopes in the induction of antitumor CD8+T-cell responses

NK Cells: Key to Success of DC-Based Cancer Vaccines?

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Molecular mimicry of MAGE-A6 andMycoplasma penetransHF-2 epitopes in the induction of antitumor CD8⁺T-cell responses