title: Dasatinib promotes Th1-type responses in granzyme B expressing T-cells.
abstract: Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of chronic myeloid leukemia (CML). Besides inhibiting target kinases in leukemic cells, 2nd generation TKI dasatinib also inhibits off-targets in immune effector cells resulting in atypical immune responses in some patients. Dasatinib has been described to increase the proportion of late effector memory T-cells, however, to date no follow-up studies have been performed in first-line patients. In this study, we explored the functional properties of T-cells using primary samples from CML patients (n = 28) on TKI therapy. Granzyme B (GrB) was used as a marker for late phase antigen experienced CD4+ and CD8+ T-cells. Dasatinib treatment increased the numbers of both GrB expressing memory CD4+ and CD8+ T-cells when compared with healthy controls. Functionally, the GrB+CD4+ T-cells were highly active and differentiated into Th1-type T-cells capable of producing IFN-γ, which is important for tumor control. Similar kind of increase was not observed during imatinib or nilotinib therapy. These data support the dual mode of action of dasatinib: potent BCR-ABL1 inhibition in leukemic cells is accompanied by the enhancement of cellular immunity, which may have implications in the long-term control of leukemia.
authors.affiliation: Hematology Research Unit Helsinki; University of Helsinki; Helsinki, Finland ; Department of Hematology; Helsinki University Central Hospital Cancer Center; Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kreutzman
authors.affiliation: Hematology Research Unit Helsinki; University of Helsinki; Helsinki, Finland ; Department of Hematology; Helsinki University Central Hospital Cancer Center; Helsinki, Finland.
authors.forename: Mette
authors.initials: M
authors.lastname: Ilander
authors.affiliation: Hematology Research Unit Helsinki; University of Helsinki; Helsinki, Finland ; Department of Hematology; Helsinki University Central Hospital Cancer Center; Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Hematology Research Unit Helsinki; University of Helsinki; Helsinki, Finland ; Department of Hematology; Helsinki University Central Hospital Cancer Center; Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Vakkila
authors.affiliation: Hematology Research Unit Helsinki; University of Helsinki; Helsinki, Finland ; Department of Hematology; Helsinki University Central Hospital Cancer Center; Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
keywords: CML; Th1-immune response; dasatinib; granzyme B; tyrosine kinase inhibitors
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