Profound inhibition of antigen-specific T-cell effector functions by dasatinib

Weichsel, Ralf, Dix, Carolin, Wooldridge, Linda, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Fenton-May, Angharad, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, Zezula, Josef, Greiner, Elizabeth, Gostick, Emma, Price, David ORCID: https://orcid.org/0000-0001-9416-2737, Einsele, Hermann and Seggewiss, Ruth 2008. Profound inhibition of antigen-specific T-cell effector functions by dasatinib. Clinical Cancer Research 14 (8) , pp. 2484-2491. 10.1158/1078-0432.CCR-07-4393

Full text not available from this repository.

Abstract

Purpose: 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. Experimental Design: 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, IFNγ, and tumor necrosis factor α), 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. Conclusion: 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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	Dasatinib ; T lymphocyte subsets ; Cytomegalovirus ; EBV
ISSN:	1078-0432
Last Modified:	27 Jul 2023 01:08
URI:	https://orca.cardiff.ac.uk/id/eprint/6164

Citation Data

Cited 127 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item