Imatinib mesylate does not impair the immunogenicity of human myeloid blood dendritic cells

Wehner, Rebekka; Wendisch, M.; Schäkel, Knut; Bornhäuser, Martin; Platzbecker, Uwe; Mohr, Brigitte; Temme, Achim; Bachmann, Michael; Rieber, Ernst Peter; Schmitz, Marc

doi:10.1038/sj.leu.2404315

Cited by 9 publications

(6 citation statements)

References 10 publications

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“…These data were further corroborated by a recent report from Wehner and co-workers demonstrating that SlanDC (i.e. native human blood DC which are not generated in vitro by culture with IL-4 and GM-CSF) from CML-patients and healthy controls are not affected by Imatinib treatment in terms of their phenotype and function [26]. These findings highlight that T-cells, rather than normal monocyte-derived or bcr-abl + CML-DC, might be the major targets for the immunomodulatory effects of Imatinib.…”

Section: Imatinib Affects Biology Of Cml-dcsupporting

confidence: 81%

The Kinase Inhibitor Imatinib - An Immunosuppressive Drug?

Wolf

Tilg²,

Rumpold³

et al. 2007

CCDT

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The phenylaminopyrimidine-derivate Imatinib mesylate has been developed for targeted inhibition of the Abelson kinase (c-ABL), which is constitutively activated when translocated to the genetic locus of the breakpoint cluster region (leading to the BCR/ABL fusion gene), thereby forming the causative pathogenetic event for the development of chronic myeloid leukemia (CML). Of note, due to its physico-chemical properties, kinase specificity of Imatinib is limited. Despite of its well documented clinical efficacy mediated by inhibition of constitutively activated tyrosine kinases such as BCR/ABL in CML, PDGF-RA in HES and mutated c-kit in GIST patients, other tyrosine kinases such as Flt-3, Lck and mitogen-activated kinases (MAPK) are affected as well. Accordingly, it has recently been shown that therapeutic doses of Imatinib also target a variety of immune cells, e.g. by modulating the differentiation of dendritic cells (DC) as well as by impeding proper T-cell and macrophage function. In contrast, combining Imatinib with Interleukin 2 (IL-2) potently activates NK-cells and led to the description of a new subclass of DC, so-called IK-DC. The latter mediate Imatinib/IL-2-induced regression of tumors in pre-clinical animal models via production of high amounts of IFN-gamma and the death receptor ligand TRAIL. Thus, Imatinib exerts potent immuno-modulatory effects in vitro and in vivo, which will be discussed together with their clinical relevance in detail throughout this review.

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Section: Imatinib Affects Biology Of Cml-dcsupporting

confidence: 81%

The Kinase Inhibitor Imatinib - An Immunosuppressive Drug?

Wolf

Tilg²,

Rumpold³

et al. 2007

CCDT

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“…In mice, DC treated with imatinib have exhibited enhanced APC function [21]. Limited studies investigating the impact of imatinib on na1ve human blood DC have revealed that imatinib impairs neither the immunophenotype profile nor the DC-mediated polarization of na1ve CD4 + T cells [22,23]. In one study, where DC were generated from CML patients treated with TKI, there was an increase of CD1a, CD80, and CD86 compared to the parent population, but not to healthy donors.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Hus

Tabarkiewicz²,

Lewandowska³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:Immunotherapy with dendritic cells (DC) may constitute a new and advantageous option for patients with chronic myeloid leukemia (CML) who respond to therapy with tyrosine kinase inhibitors (TKI), but do not reach complete cytogenetic or molecular remission. In this study, we evaluated the immunophenotype of DC generated from monocytes (Mo-DC) of patients with CML and the influence of TKI therapy on the results of CML-DC generation. We also measured the percentages of T regulatory cells (Tregs) as well as Th17 cells in 19 untreated patients suffering from CML, and in 28 CML patients treated with TKI. We found that DC can be reliably generated from the peripheral blood CD14 + cells of untreated CML patients. But we observed a persistent expression of CD14 monocyte marker on DC from CML patients, together with lower percentages of Mo-DC with expression of CD1a (p = 0.002), CD80 (p = 0.0005), CD83 (p = 0.0004), and CD209 (p = 0.02) compared to healthy donors. There was an adverse correlation between WBC count and the percentage of Mo-DC with co-expression of CD80 and CD86 (R = -0.63; p = 0.03). In patients treated with TKI, we observed higher efficacy of DC generation in seven-day cultures, compared to untreated patients. Expression of CD209 on DC was higher in patients treated with TKI (0.02). The duration of TKI therapy correlated adversely with MFI for CD1a (R = -0.49; p = 0.006) and positively with MFI for CD83 (R = 0.63; p = 0.01). Percentages of CD4 + CD25 high FoxP3 + cells (p = 0.0002) and Th17 cells (p = 0.02) were significantly higher in untreated CML patients compared to healthy controls. There was a significant correlation between the percentage of Treg cells and the percentage of peripheral blood basophiles (R = 0.821; p = 0.02). There were no changes in Tregs or Th17 cell percentages in CML patients after six months of TKI therapy. However, the expression of intracellular IL-17 in Th17 cells correlated negatively with the time of TKI therapy in the whole group of treated patients (R = -0.516; p = 0.04). We noted a correlation between IL-6 serum level and peripheral blood WBC count (R = 0.492; p = 0.04). There was also an inverse correlation between the serum level of IL-6 and the duration of TKI therapy (R = -0.66; p = 0.03). Taken together, our data shows that mature DC can be generated from CML patients treated with TKI, and that the yield of Mo-DC is higher in patients treated with TKI than in patients with active disease. This should encourage further trials with DC immunotherapy in patients with cytogenetic response after TKI therapy. We also found increased frequencies of T regulatory and Th17 cells in CML patients, which might suggest their potential role in immunity against 154

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“…48 Recent studies revealed the capability of human DCs to promote NK cell proliferation, IFN-g-secretion and tumor-directed cytotoxicity. 15,49,50 Following our observation that slanDCs can also efficiently trigger NK cells 34,44 and previous reports demonstrating effective NK cell-mediated lysis of myeloma cells, 51,52 we determined whether bortezomib influences the capability of slanDCs to activate these innate effector cells. Therefore, bortezomib-pretreated DCs were cocultured with immunomagnetically purified autologous CD56 þ CD3À NK cells in the presence of LPS for 18 h. As demonstrated in Figure 5, bortezomib significantly reduced the ability of LPS-activated slanDCs to improve IFN-g production by NK cells.…”

Section: Impact Of Bortezomib On Blood Dendritic Cells C Straube Et Almentioning

confidence: 99%

“…32,44 To determine whether bortezomib inhibits this functional property bortezomib-preincubated slanDCs were cocultured with allogeneic naïve CD45RA þ CD4 þ T cells in the presence of LPS. Thereafter, T cells were stimulated with PMA and ionomycin and evaluated for IFN-g and IL-4 production.…”

Section: Impact Of Bortezomib On Blood Dendritic Cells C Straube Et Almentioning

confidence: 99%

Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells

et al. 2007

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Bortezomib is a potent drug for the treatment of multiple myeloma. Its anti-tumor activity is mediated by proteasome inhibition leading to decreased cell proliferation and induction of apoptosis. However, an unimpaired proteasomal function plays a crucial role for the induction of anti-tumor immunity by dendritic cells (DCs), which are currently used for therapeutic vaccination against various tumors including myeloma. In the present study, we investigated the impact of bortezomib on the immunostimulatory capacity of 6-sulfo LacNAc (slan) DCs, which represent a major subset of human blood DCs. We demonstrated that this proteasome inhibitor efficiently impairs the spontaneous in vitro maturation of slanDCs and the release of tumor necrosis factor (TNF)-a as well as interleukin (IL)-12 upon lipopolysaccharide (LPS) stimulation. Functional data revealed that bortezomib profoundly inhibits slanDC-induced proliferation and differentiation of CD4 þ T cells. In addition, the capacity of slanDCs to promote interferon-c secretion and tumor-directed cytotoxicity of natural killer (NK) cells is markedly impaired by bortezomib. These results provide evidence that bortezomib significantly reduces the ability of native human blood DCs to regulate innate and adaptive antitumor immunity and may have implications for the design of therapeutic strategies combining DC vaccination and bortezomib treatment.

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Imatinib mesylate does not impair the immunogenicity of human myeloid blood dendritic cells

Cited by 9 publications

References 10 publications

The Kinase Inhibitor Imatinib - An Immunosuppressive Drug?

The Kinase Inhibitor Imatinib - An Immunosuppressive Drug?

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells

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