title: The tyrosine kinase inhibitors imatinib and dasatinib reduce myeloid suppressor cells and release effector lymphocyte responses.
abstract: 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 inhibitory molecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naïve/memory), and stimulatory cytokines (IL12, IFNγ, 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 IFNγ 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratories, Uppsala University, Uppsala, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Christiansson
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Section of Hematology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Söderlund
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratories, Uppsala University, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Mangsbo
authors.affiliation: Department of Hematology, St. Olav's Hospital, Trondheim, Norway. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU) Trondheim, Norway.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Section of Hematology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.affiliation: Department of Hematology, Norrland University Hospital, Umeå, Sweden.
authors.forename: Berit
authors.initials: B
authors.lastname: Markevärn
authors.affiliation: Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.affiliation: Department of Hematology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
authors.affiliation: Hematology Research Unit Helsinki, Department of Medicine, Division of Hematology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratories, Uppsala University, Uppsala, Sweden. angelica.loskog@igp.uu.se.
authors.forename: Angelica
authors.initials: A
authors.lastname: Loskog
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Section of Hematology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Olsson-Strömberg
mesh_terms: D000328:Adult; D000368:Aged; D039481:CD11b Antigen / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D039481:CD11b Antigen; C571163:CD33 protein, human; C509295:ITGAM protein, human; D018950:Lipopolysaccharide Receptors; D047428:Protein Kinase Inhibitors; D063268:Sialic Acid Binding Ig-like Lectin 3; D000068877:Imatinib Mesylate; D000069439:Dasatinib