Dasatinib enhances migration of monocyte-derived dendritic cells by reducing phosphorylation of inhibitory immune receptors Siglec-9 and Siglec-3

Nerreter, Thomas; Köchel, Christoph; Jesper, Daniel; Eichelbrönner, Irina; Putz, Evelyn; Einsele, Hermann; Seggewiss‐Bernhardt, Ruth

doi:10.1016/j.exphem.2014.05.010

Cited by 10 publications

(7 citation statements)

References 46 publications

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“…Wolfl et al ( 17 ) observed that dasatinib significantly improved the production of IL-12p70 during TLR2/4-triggered DC activation. Nerreter et al ( 18 ) found that the number of migratory DCs in a dasatinib-pretreated LPS-matured DC cohort was significantly increased compared with the LPSonly-matured DC cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, dasatinib enhanced the therapeutic efficacy of the DC vaccine in vitro and in vivo ( 8 , 17 – 19 ). Nerreter et al ( 18 ) reported that dasatinib enhanced the migration of DCs without changing the ability to prime and boost antigen-specific T cell response by reducing the phosphorylation of inhibitory immune receptor siglec-9 and siglec-3 in vitro using human peripheral blood mononuclear cell-derived DCs. Lowe et al ( 8 ) revealed that dasatinib combined with the DC vaccine significantly reduced tumor volume, with enhanced recruitment of CD8 + T cells and DCs to tumor-draining lymph nodes and the tumor microenvironment in M05 melanoma mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic anti-tumor effects of dasatinib and dendritic cell vaccine onmetastatic breast cancer in a mouse model

et al. 2018

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Immunotherapy is currently considered as one of the major anti-tumor modalities, but its efficacy is limited. Dasatinib could improve the expansion and recruitment of cluster of differentiation (CD) 8+T cells and natural killer (NK) cells to the tumor microenvironment. The present study aimed to evaluate the synergistic anti-tumor effects of dasatinib with dendritic cell (DC) vaccine in metastatic breast cancer. Dasatinib with DC vaccine was administered to mice inoculated with 4T1 breast cancer cells. Thereafter, tumor volume was measured every other day. On day 34, lung metastasis was assessed with a stereomicroscope. Tumor proliferation and angiogenesis were determined by immunohistochemistry. Apoptosis in tumor tissues was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling. The results showed that although there were no significant differences in tumor volumes between the untreated control, DC vaccine and dasatinib groups, the tumor volume was significantly decreased in the combined treatment group compared to the other three groups. Mice in the combined treatment group showed the longest survival time, while mice treated with either single treatment had a slightly increased survival time compared to the untreated control mice. Additionally, the number of metastatic lung nodules was significantly decreased in combined treatment group compared with the dasatinib alone, DC vaccine alone and untreated control groups. Furthermore, the combined treatment group showed significantly reduced intratumoral microvessel density compared to the other three groups. In addition, the ratios of CD8+ T and NK cells were significantly increased in the combined treatment group compared with the other three groups. These results suggest that dasatinib combined with the DC vaccine is a possible modality for the treatment of metastatic breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synergistic anti-tumor effects of dasatinib and dendritic cell vaccine onmetastatic breast cancer in a mouse model

et al. 2018

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“…Tyrosine kinases also shape innate immune responses by interfering with Toll like receptor signaling, phagocytosis and the maturation of monocytes possibly by the up‐regulation of the inhibitory receptor osteoactivin . Accordingly, TKIs have multiple effects on the function of myeloid cells, including myelopoiesis , cytokine release , migration of dendritic cells , inflammation and related tissue damage , autophagy , lysosomal acidification and antimicrobial activity . Considering the diverse functions controlled by Abl/Src kinases it is unexpected, that severe infections related to TKI‐treatment are exceptional .…”

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abltyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification inMtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. Keywords: Human primary cells r infection immunology r infection immunology r tuberculosis r T-cells r Tyrosine kinase inhibitorAdditional supporting information may be found online in the Supporting Information section at the end of the article.

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“…The ligation of Siglec-9 with specific blocking antibodies [87] or using the Siglec-9 phosphorylation inhibitor dasatinib [88] could significantly decrease the production of IL-12 and enhance the migration of monocyte-derived DCs. It is generally believed that DCs play an important role in T helper immunity and IL-12 is also involved in the differentiation of Th0 cells into Th1 cells [89], suggesting that targeting Siglec-9 has a potential role in improving DCrelated immunotherapeutic approaches.…”

Section: Natural Ligands For Siglec-9 and Siglec-ementioning

confidence: 99%

Targeting Neutrophils in Severe Asthma via Siglec-9

Chen

Bai

Han

et al. 2018

Int Arch Allergy Immunol

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Severe asthma comprises only 5% of patients with asthma, but the burden it brings to the social health system accounts for more than half of all asthmatics. Clinical evidence shows that severe asthma is often linked to the recruitment and activation of neutrophils in the airways. However, the underlying molecular and immunological mechanisms of neutrophilia in severe asthma are not clear and currently available drugs exert only limited effects on neutrophilic inflammation. Great efforts are underway to address the mystery of neutrophilic inflammation in chronic respiratory disorders. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are members of the immunoglobulin gene family. Of note, Siglec-9 is uniquely expressed by human neutrophils and monocytes, as well as a minor population of natural killer cells. Engaging this structure with antibodies or glycan ligands results in programmed cell death in human neutrophils. Intriguingly, the administration of Siglec-E antibody abolished the recruitment of neutrophils in mouse models of neutrophilic pulmonary inflammation in vivo. Given that neutrophils are probably a major culprit in the generation and perpetuation of inflammation, targeting Siglec-9 could be beneficial for the treatment of severe asthma, chronic obstructive pulmonary disease, and related pulmonary disorders characteristic of neutrophilia.

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Dasatinib enhances migration of monocyte-derived dendritic cells by reducing phosphorylation of inhibitory immune receptors Siglec-9 and Siglec-3

Cited by 10 publications

References 46 publications

Synergistic anti-tumor effects of dasatinib and dendritic cell vaccine onmetastatic breast cancer in a mouse model

Synergistic anti-tumor effects of dasatinib and dendritic cell vaccine onmetastatic breast cancer in a mouse model

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

Targeting Neutrophils in Severe Asthma via Siglec-9

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