Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Abstract

Abstract:Immunotherapy with dendritic cells (DC) may constitute a new and advantageous option for patients with chronic myeloid leukemia (CML) who respond to therapy with tyrosine kinase inhibitors (TKI), but do not reach complete cytogenetic or molecular remission. In this study, we evaluated the immunophenotype of DC generated from monocytes (Mo-DC) of patients with CML and the influence of TKI therapy on the results of CML-DC generation. We also measured the percentages of T regulatory cells (Tregs) as well as Th17 cells in 19 untreated patients suffering from CML, and in 28 CML patients treated with TKI. We found that DC can be reliably generated from the peripheral blood CD14 + cells of untreated CML patients. But we observed a persistent expression of CD14 monocyte marker on DC from CML patients, together with lower percentages of Mo-DC with expression of CD1a (p = 0.002), CD80 (p = 0.0005), CD83 (p = 0.0004), and CD209 (p = 0.02) compared to healthy donors. There was an adverse correlation between WBC count and the percentage of Mo-DC with co-expression of CD80 and CD86 (R = -0.63; p = 0.03). In patients treated with TKI, we observed higher efficacy of DC generation in seven-day cultures, compared to untreated patients. Expression of CD209 on DC was higher in patients treated with TKI (0.02). The duration of TKI therapy correlated adversely with MFI for CD1a (R = -0.49; p = 0.006) and positively with MFI for CD83 (R = 0.63; p = 0.01). Percentages of CD4 + CD25 high FoxP3 + cells (p = 0.0002) and Th17 cells (p = 0.02) were significantly higher in untreated CML patients compared to healthy controls. There was a significant correlation between the percentage of Treg cells and the percentage of peripheral blood basophiles (R = 0.821; p = 0.02). There were no changes in Tregs or Th17 cell percentages in CML patients after six months of TKI therapy. However, the expression of intracellular IL-17 in Th17 cells correlated negatively with the time of TKI therapy in the whole group of treated patients (R = -0.516; p = 0.04). We noted a correlation between IL-6 serum level and peripheral blood WBC count (R = 0.492; p = 0.04). There was also an inverse correlation between the serum level of IL-6 and the duration of TKI therapy (R = -0.66; p = 0.03). Taken together, our data shows that mature DC can be generated from CML patients treated with TKI, and that the yield of Mo-DC is higher in patients treated with TKI than in patients with active disease. This should encourage further trials with DC immunotherapy in patients with cytogenetic response after TKI therapy. We also found increased frequencies of T regulatory and Th17 cells in CML patients, which might suggest their potential role in immunity against 154

Defective Generation and Maturation of Dendritic Cells from Monocytes in Colorectal Cancer Patients during the Course of Disease

“…Therefore, our results show that CRC exerts negative effects on DC generation and maturation at a systemic level and that both of these deficiencies appear to correlate with the disease stage. These observations agree with those of previous studies on different tumor types [20–22,24,47,48]. Conversely, Gabrilovich et al showed that DCs isolated from breast cancer patient blood samples are impaired with regard to phenotypic features and in vitro antigen presentation, whereas DCs generated in vitro from blood precursors in the same patient samples are totally functional; the authors concluded that defective DC function can be at least partially overcome by removing the tumor immunosuppressive factors and generating DCs in vitro [49].…”

Myeloid Derived Suppressor Cells (MDSCs) Are Increased and Exert Immunosuppressive Activity Together with Polymorphonuclear Leukocytes (PMNs) in Chronic Myeloid Leukemia Patients

“…Since MDSCs drive the development of T-reg [21], [22], [34], in some patients we also investigated the levels of circulating T-reg cells. As it has been reported [35], [36], in CML patients T-reg resulted significantly increased in respect to HD and we found that they directly correlated with Gr-MDSCs. Similar to Gr-MDSCs, the percentage of T-reg cells decreased to the HD levels after TKI therapy, confirming the correlation with the amount of granulocytic MDSCs.…”

Regulatory T Cells and Their Prognostic Relevance in Hematologic Malignancies

“…Rojas et al found a lower Treg number in patients who achieved a complete cytogenetic response [ 63 ], while higher Treg frequencies were found after stem cell transplant compared to normal controls and newly diagnosed patients [ 64 ]. Finally, the correlations with Sokal score and basophil number were validated by other studies [ 65 , 66 ], whereas the impact of treatment has not been confirmed, since no changes in Treg frequency was observed after 6 months of tyrosine kinase inhibitors therapy [ 65 ]. Table 5 summarizes the results of studies analyzing Tregs in CML.…”