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The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses

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Author

  • Lisa Christiansson
  • Stina Soderlund
  • Sara Mangsbo
  • Henrik Hjorth-Hansen
  • Martin Hoglund
  • Berit Markevarn
  • Johan Richter
  • Leif Stenke
  • Satu Mustjoki
  • Angelica Loskog
  • Ulla Olsson-Stromberg
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Summary, in English

Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy.

Publishing year

2015

Language

English

Pages

1181-1191

Publication/Series

Molecular Cancer Therapeutics

Volume

14

Issue

5

Document type

Journal article

Publisher

American Association for Cancer Research

Topic

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1538-8514