Therapeutic immune monitoring of CD4(+)CD25(+) T cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib, are effective forms of therapy for various types of solid cancers and Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia. A number of TKIs have been known to have strong effects on T cells, particularly cluster of differentiation (CD) 4(+)CD25(+) T cells, also known as regulatory T cells (Tregs). There is currently a deficit in the available clinical data regarding this area of study. In the present study, a total of 108 peripheral blood samples were collected from patients with chronic myeloid leukemia (CML) at diagnosis (n=31), and at 3 and 6 months following treatment with TKI [imatinib (n=12), dasatinib (n=11) and nilotinib groups (n=8)] and healthy controls (n=15). Peripheral blood mononuclear cells were collected from the patients prior to and following TKI treatment. The subtype and number of T lymphocytes in patients and healthy donors were analyzed using flow cytometry. Additionally, flow cytometry and ELISA were used to detect the proliferation and suppression of Tregs. Expression of cytokines and other molecules [forkhead box P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)] were also analyzed at 3 and 6 months following treatment with TKIs. It was indicated that, at diagnosis, a similar number of lymphocytes were detected in patients and control. However, following treatment with a TKI, the number of total T cells, Tregs, CD4(+) T and CD8(+) T cells decreased to various degrees in patients. Furthermore, the decrease in the number of Tregs was more significant with time. Although treatment with imatinib, dasatinib and nilotinib demonstrated similar inhibitory effects on the quantity of Tregs in vivo, the TKIs exhibited differential effects on the function of Tregs in vitro. Proliferation, suppression and expression of cytokines [interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-β] and molecules (FOXP3, GITR and CTLA-4) decreased significantly in treatment groups with imatinib and dasatinib. The decrease was not significant in the nilotinib treatment group. Imatinib and dasatinib may exert more marked inhibitory roles compared with nilotinib on regulating the number and function of Tregs. These results suggest that personalized treatment and follow-up of CML patients during TKI treatment, particularly for those who received post-transplant TKI treatment may be beneficial.