Profound inhibition of antigen-specific T-cell effector functions by dasatinib.
OBJECTIVE
The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator.


METHODS
Purified human CD3+ cells and virus-specific CD8+ T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFN gamma, and tumor necrosis factor alpha), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction.


RESULTS
Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4+ T cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve T cells more sensitive than memory T-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations.


CONCLUSIONS
These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell-driven autoimmune diseases.
Weichsel
Ralf
R
Immune Recovery Section, Med. Klinik und Poliklinik II, University of Würzburg, Würzburg, Germany.
Dix
Carolin
C
Wooldridge
Linda
L
Clement
Matthew
M
Fenton-May
Angharad
A
Sewell
Andrew K
AK
Zezula
Josef
J
Greiner
Elisabeth
E
Gostick
Emma
E
Price
David A
DA
Einsele
Hermann
H
Seggewiss
Ruth
R
D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology*
D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D013844:Thiazoles; D019311:Staurosporine; D000069439:Dasatinib