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Innate T-αβ lymphocytes as new immunological components of anti-tumoral "off-target" effects of the tyrosine kinase inhibitor dasatinib

Abstract : Kinase inhibitors hold great potential as targeted therapy against malignant cells. Among them, the tyrosine kinase inhibitor dasatinib is known for a number of clinically relevant off-target actions, attributed in part to effects on components of the immune system, especially conventional T-cells and natural killer (NK)-cells. Here, we have hypothesized that dasatinib also influences non-conventional T-αβ cell subsets known for their potential anti-tumoral properties, namely iNKT cells and the distinct new innate CD8 T-cell subset. In mice, where the two subsets were originally characterized, an activated state of iNKT cells associated with a shift toward an iNKT cell Th1-phenotype was observed after dasatinib treatment in vivo. Despite decreased frequency of the total memory CD8 T-cell compartment, the proportion of innate-memory CD8 T-cells and their IFNγ expression in response to an innate-like stimulation increased in response to dasatinib. Lastly, in patients administered with dasatinib for the treatment of BCR-ABL-positive leukemias, we provided the proof of concept that the kinase inhibitor also influences the two innate T-cell subsets in humans, as attested by their increased frequency in the peripheral blood. These data highlight the potential immunostimulatory capacity of dasatinib on innate T-αβ cells, thereby opening new opportunities for chemoimmunotherapy.
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Submitted on : Wednesday, March 4, 2020 - 11:20:25 AM
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Alice Barbarin, Myriam Abdallah, Lucie Lefèvre, Nathalie Piccirilli, Emilie Cayssials, et al.. Innate T-αβ lymphocytes as new immunological components of anti-tumoral "off-target" effects of the tyrosine kinase inhibitor dasatinib. Scientific Reports, 2020, 10 (1), pp.3245. ⟨10.1038/s41598-020-60195-z⟩. ⟨inserm-02498183⟩



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