Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells

Smits, Evelien; Ponsaerts, Peter; Velde, Ann L.R. Van de; Driessche, Ann Van; Cools, Nathalie; Lenjou, Marc; Nijs, Griet; Bockstaele, Dirk R. Van; Berneman, Zwi N.; Tendeloo, Viggo Van

doi:10.1038/sj.leu.2404763

Cited by 43 publications

(37 citation statements)

References 39 publications

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“…As previously described by our group, DCs loaded with apoptotic HSP70-expressing M13 cells and activated by exogenous maturation agents are potent in vitro inducers of mesothelioma-specific CTLs (23). Interestingly, recent studies indicated a relevant adjuvant effect of cellular-associated dsRNA for tumor cells loaded with poly(I:C) (46,47) and for virally Semliki Forest virus-infected Vero cells (48). So, although not directly correlated by our results, we hypothesize that apoptotic mesothelioma cells loaded with viral dsRNA produced by MV infection might be a strong immunogenic signal, leading to the spontaneous maturation of monocyte-derived DCs and the subsequent activation of a relevant MSLN-specific CD8 T-cell response.…”

Section: Cancer Researchmentioning

confidence: 58%

Measles Virus Induces Oncolysis of Mesothelioma Cells and Allows Dendritic Cells to Cross-Prime Tumor-Specific CD8 Response

et al. 2008

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Despite conventional medical and surgical treatments, malignant pleural mesothelioma (MPM) remains incurable. Oncovirotherapy (i.e., the use of replication-competent virus for cancer treatment) is currently explored in clinical trials. In this study, we investigated the antineoplastic potential of a new oncolytic viral agent, a live-attenuated measles virus (MV) strain derived from the Edmonston vaccine lineage (Schwarz strain). We evaluated both oncolytic activity and immunoadjuvant properties of the MV vaccine strain on mesothelioma tumor cells. Infectivity, syncytium formation, and cytolytic activity of MV were studied on a panel of mesothelioma cells derived from pleural effusions of MPM patients. We observed that MV infected preferentially MPM cell lines in comparison with nontransformed mesothelial cells, leading to an efficient killing of a significant fraction of tumor cells. A cytoreductive activity was also evidenced through formation of multinuclear cellular aggregates (syncytia). The susceptibility of MPM cell lines to measles infection was assessed by the analysis of cell surface expression of the MV vaccine receptor (CD46). We also evaluated whether MV infection of mesothelioma cells could elicit an autologous antitumor immune response. We showed that MV Schwarz strain induced apoptotic cell death of infected mesothelioma cells, which were efficiently phagocytosed by dendritic cells (DC). Loading of DCs with MV-infected MPM cells induced DC spontaneous maturation, as evidenced by the increased expression of MHC and costimulatory molecules along with the production of proinflammatory cytokines. Priming of autologous T cells by DCs loaded with MV-infected MPM cells led to a significant proliferation of tumor-specific CD8 T cells. Altogether, these data strongly support the potential of oncolytic MV as an efficient therapeutic agent for mesothelioma cancer. [Cancer Res 2008;68(12):4882-92]

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Section: Cancer Researchmentioning

confidence: 58%

Measles Virus Induces Oncolysis of Mesothelioma Cells and Allows Dendritic Cells to Cross-Prime Tumor-Specific CD8 Response

et al. 2008

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“…We have previously reported that AML cells in response to electroporation with poly(I:C) show improved tumor cell immunogenicity, demonstrated by an enhanced capacity to activate and mature DC [53] and induce the release of NK cell IFN-γ [78]. Ensuing from these data, in this study, we examined the effect of poly(I:C)-electroporated AML cells on the phagocytic capacity of immature DC and on the cytotoxic function of NK cells.…”

Section: Introductionmentioning

confidence: 91%

“…Poly(I:C) is an agonist of the innate endosomal TLR3 and the cytosolic melanoma differentiation-antigen-5 (mda-5) receptors [47]. It is a well-described danger signal able to trigger cell death and induce the production of proinflammatory cytokines, including type I interferons (IFN), in various cell types [47]–[53]. Under defined conditions, poly(I:C) is a powerful NK cell activation signal [47], [52], [54]–[60] and it has been shown to efficiently activate and mature DC [61]–[66] and stimulate DC-NK cell interactions [55], [67], [68].…”

Section: Introductionmentioning

confidence: 99%

Poly(I:C) Enhances the Susceptibility of Leukemic Cells to NK Cell Cytotoxicity and Phagocytosis by DC

et al. 2011

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α Active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.

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“…For AML, it is not yet clear whether cell lysates or apoptotic cells are preferable for Ag loading onto MoDC [9, 19–25]. Next to enhancing immunogenicity of tumor Ag sources by, for instance, heat shock, addition of DC-maturing stimuli, such as Toll-like receptor ligands (TLR-L), is explored; e.g., electroporation of TLR3-L Poly(I:C) into AML cells results in enhanced uptake of leukemic cells by DC and improves their subsequent maturation and cytokine production [26]. Furthermore, intracellular binding of TLR8 by its ligand R848 has been reported to result in enhanced cross-priming of exogenous Ag by MoDC [27].…”

Section: Introductionmentioning

confidence: 99%

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

Ancker

Luijn

Ruben

et al. 2010

Cancer Immunol Immunother

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Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1β, IL-6, TNF-α, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by the TLR7/8-L R848 (20–30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides. To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24 h followed by addition of CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation.

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Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells

Cited by 43 publications

References 39 publications

Measles Virus Induces Oncolysis of Mesothelioma Cells and Allows Dendritic Cells to Cross-Prime Tumor-Specific CD8 Response

Measles Virus Induces Oncolysis of Mesothelioma Cells and Allows Dendritic Cells to Cross-Prime Tumor-Specific CD8 Response

Poly(I:C) Enhances the Susceptibility of Leukemic Cells to NK Cell Cytotoxicity and Phagocytosis by DC

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

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