Lck is a key target of imatinib and dasatinib in T-cell activation

Lee, K C; Ouwehand, I; Giannini, Ana L.M.; Thomas, Nancy; Dibb, Nick J.; Bijlmakers, Marie-José

doi:10.1038/leu.2010.11

Cited by 77 publications

(73 citation statements)

References 11 publications

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“…Dasatinib inhibits TCR triggering in T cells by blocking the src-kinase Lck. 38 However, studies addressing the effects of tyrosine kinase inhibitors on DCs are controversial. 18 Our data now clearly demonstrate a stimulatory mechanism for dasatinib and other src-kinase inhibitors, which is strictly dependent on the mode of DC activation, suggesting interference with specific regulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Wölfl

Schwinn²,

Yoo

et al. 2013

Blood

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• In contrast to their suppressive effects on T cells, src-kinase inhibitors strongly enhance IL-12 production in human myeloid cells. • This effect is synergistic to TLR2 or TLR4 signaling, whereas inhibition of srckinases alone does not trigger DC activation.Src-kinase inhibitors hold great potential as targeted therapy against malignant cells. However, such inhibitors may also affect nonmalignant cells and cause pronounced offtarget effects. We investigated the role of the dual kinase inhibitor dasatinib on human myeloid cells. Dasatinib is clinically used for the treatment of bcr/abl 1 leukemias because it blocks the mutated tyrosine kinase abl. To understand its effect on the development of antigen-specific T-cell responses, we assessed antigen-specific priming of human, naïve T cells. In surprising contrast to the direct inhibition of T-cell activation by dasatinib, pretreatment of maturing dendritic cells (DCs) with dasatinib strongly enhanced their stimulatory activity. This effect strictly depended on the activating DC stimulus and led to enhanced interleukin 12 (IL-12) production and T-cell responses of higher functional avidity. Src-kinase inhibitors, and not conventional tyrosine kinase inhibitors, increased IL-12 production in several cell types of myeloid origin, such as monocytes and classical or nonclassical DCs. Interestingly, only human cells, but not mouse or macaques DCs, were affected. These data highlight the potential immunostimulatory capacity of a group of novel drugs, src-kinase inhibitors, thereby opening new opportunities for chemoimmunotherapy. These data also provide evidence for a regulatory role of src kinases in the activation of myeloid cells. (Blood. 2013;122(7):1203-1213

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Section: Discussionmentioning

confidence: 99%

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Wölfl

Schwinn²,

Yoo

et al. 2013

Blood

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“…We found, however, that GTPCH-1 expression was increased by anti-CD3 even when IL-2 was excluded from the media, indicating that this cytokine does not significantly alter GTPCH-1 expression (data not shown). An important downstream signaling event of T cell receptor ligation is activation of the tyrosine kinase Lck, which is inhibited by dasatinib (25). Addition of dasatinib during exposure to anti-CD3 completely abrogated the increase in GTPCH-1 protein (Fig.…”

Section: Was Greater In Cd8mentioning

confidence: 93%

Role of Increased Guanosine Triphosphate Cyclohydrolase-1 Expression and Tetrahydrobiopterin Levels upon T Cell Activation

Chen

Brod

et al. 2011

Journal of Biological Chemistry

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“…11,22,23 We characterized T-and B-cell responses to vaccination against influenza and pneumococcus in CP-CML patients receiving imatinib, dasatinib, and nilotinib and healthy controls. We found that the B-cell response to pneumococcal vaccine is significantly impaired in CML patients, associated with loss of memory B-cell subsets.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

Lavallade

Khoder

Hart

et al. 2013

Blood

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Key Points• TKIs impair B-cell immune responses in CML through off-target inhibition of kinases important for B-cell signaling.• Our results call for close monitoring of patients on TKI to assess the long-term impact of impaired B-cell function.Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P 5 .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-g2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML. (Blood. 2013;122(2):227-238)

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Lck is a key target of imatinib and dasatinib in T-cell activation

Cited by 77 publications

References 11 publications

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Role of Increased Guanosine Triphosphate Cyclohydrolase-1 Expression and Tetrahydrobiopterin Levels upon T Cell Activation

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

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