Effects of dasatinib on CD8⁺T, Th1, and Treg cells in patients with chronic myeloid leukemia

Abstract

To investigate the immunomodulatory effects of the tyrosine kinase inhibitor (TKI) dasatinib on T-cell subtypes in patients with chronic myeloid leukemia (CML). Methods: T helper (Th) 1, Th2, regulatory T (Treg), and CD8 þ T cell levels were detected in patients with CML (n ¼ 9) before and after dasatinib treatment. The corresponding response level at the time of a blood test was evaluated. Results: After dasatinib treatment, six patients achieved a better response level, while three did not show improved response levels. Among the total nine patients, there were no significant differences in Th1, Th2, and Treg cell levels, whereas CD8 þ T cell levels were significantly increased after dasatinib treatment compared with before treatment. When we analyzed the six patients who obtained a better response level, Th1 and CD8 þ T cell levels were significantly increased after dasatinib treatment, but Th2 and Treg cell levels did not change. The other three patients who did not have improved response levels showed decreased Th1 cell levels and increased Treg cell levels after treatment. Conclusions: Dasatinib may increase Th1 and CD8 þ T cell levels, and decrease Treg cell levels in patients with CML. This finding might be associated with a good therapeutic response to this drug.

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

“…Aside from early work revealing the generation of LGL in dasatinib-treated patients 15,16 , very few studies have studied dasatinib action on CD8 T-cells. However, the study by Kreutzman et al, which showed that dasatinib treatment increased the numbers of granzyme B expressing memory CD4 and CD8 T-cells 12 , and the recent study by Wei et al showing an increase of CD8 T-cells concomitantly with decreased Treg 11 , are in accordance with our own results showing an increased CD49d expression level on innate CD8 T-cells. Indeed, we have previously shown that innate CD8 T-cells have a higher cytotoxic potential than conventional CD8 T-cells 27,28 and that the IFNγ secretion function is correlated with the expression of CD49d 26 .…”

“…For example, in melanoma, sarcoma, colon and breast cancer-bearing mice, dasatinib increases CD8 T-cells concomitantly with decrease in regulatory CD4 T-cells 10 . Recently, the same effect was observed in some patients with chronic myeloid leukemia (CML) 11 . In clinical use, immunostimulatory effects have been observed during long-term use of dasatinib [12][13][14][15] .…”

Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach

“…While dasatinib is recognized as the suitable candidate due to its targeting multiple kinases involved in immune-oncogenic pathways, it shows promise in modulating the tumor immune microenvironment as well. Dasatinib treatment increased Th1 and CD8+T cell levels in patients with chronic myeloid leukemia who had better therapeutic responses [ 37 ]. Currently, dasatinib is being investigated for isocitrate dehydrogenase (IDH)-mutant advanced intrahepatic cholangiocarcinoma (NCT02428855).…”

Novel Treatment Strategies Utilizing Immune Reactions against Chronic Myelogenous Leukemia Stem Cells

“…Ishiyama et al recently reported that CD56 − NK cells with PD-1 expression were induced by chronic activation through CMV reactivation in CML or Ph + ALL patients during dasatinib therapy [ 43 ]. Interestingly, the expansion of CD56 − NK cells was associated with a higher rate of DMR, and Wei et al also reported that dasatinib increased the percentage of Th1 and CD8 T cells and decreased Treg cell levels in the peripheral blood of CML patients who responded to therapy [ 44 ]. Overall, dasatinib seems to have the potential to enhance both innate and adaptive immunity to eradicate CML-LSCs in some patients.…”