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

Hugues de Lavallade, Ahmad Khoder, Melanie Hart, Anushruti Sarvaria, Takuya Sekine, Abdullah Alsuliman, Stephan Mielke, Alexandra Bazeos, Kate Stringaris, Sara Ali, Dragana Milojkovic, Letizia Foroni, Aristeidis Chaidos, Nichola Cooper, Ian Gabriel, Jane Apperley, Sarah Belsey, Bob Flanagan, John Goldman, Elizabeth J. ShpallPeter Kelleher, David Marin, Katayoun Rezvani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

Abstract

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 = .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-gamma 2, 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.

Original languageEnglish
Pages (from-to)227-238
Number of pages12
JournalBlood
Volume122
Issue number2
DOIs
Publication statusPublished - 11 Jul 2013

Keywords

  • CHRONIC MYELOID-LEUKEMIA
  • COMMON VARIABLE IMMUNODEFICIENCY
  • LYMPHOCYTES IN-VITRO
  • CD8(+) T-CELLS
  • IMATINIB MESYLATE
  • DASATINIB THERAPY
  • CHRONIC-PHASE
  • ACTIVATION
  • DISEASE
  • PROLIFERATION

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