Development, Function, and Clinical Significance of Plasmacytoid Dendritic Cells in Chronic Myeloid Leukemia

Abstract

Plasmacytoid dendritic cells (pDC) are the main producers of a key T-cell-stimulatory cytokine, IFNα, and critical regulators of antiviral immunity. Chronic myeloid leukemia (CML) is caused by BCR-ABL, which is an oncogenic tyrosine kinase that can be effectively inhibited with ABL-selective tyrosine kinase inhibitors (TKI). BCR-ABL-induced suppression of the transcription factor interferon regulatory factor 8 was previously proposed to block pDC development and compromise immune surveillance in CML. Here, we demonstrate that pDCs in newly diagnosed CML (CML-pDC) develop quantitatively normal and are frequently positive for the costimulatory antigen CD86. They originate from low-level -expressing precursors. CML-pDCs also retain their competence to maturate and to secrete IFN. RNA sequencing reveals a strong inflammatory gene expression signature in CML-pDCs. Patients with high CML-pDC counts at diagnosis achieve inferior rates of deep molecular remission (MR) under nilotinib, unless nilotinib therapy is combined with IFN, which strongly suppresses circulating pDC counts. Although most pDCs are-negative in MR, a substantial proportion of CML-pDCs persists under TKI treatment. This could be of relevance, because CML-pDCs elicit CD8 T cells, which protect wild-type mice from CML. Together, pDCs are identified as novel functional DC population in CML, regulating antileukemic immunity and treatment outcome in CML. CML-pDC originates from low-level BCR-ABL expressing stem cells into a functional immunogenic DC-population regulating antileukemic immunity and treatment outcome in CML. .

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

“…Immunologic mechanisms are often invoked but, at present, they remain hypothetical [ 59 , 60 , 61 ]. Some evidence on a specific role of lymphocyte sub populations (NK) has been reported, but deeper studies of the immunologic mechanisms in CML patients during TKI treatment should be addressed [ 62 , 63 ]. Combinations of TKIs with other drugs having different mechanisms of action should be tested, even if no new effective molecules with this potential are currently available and, in any case, the combinations tested “in vitro” must be safe “in vivo”.…”

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV

“…For example, immuno-biological features such as CD86 + plasmacytoid dendritic cell counts were recently shown to be associated with both TFR rate and rapid, deep MR under TKI therapy. 31,32…”

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

“… 77 , 81 , 82 Conversely, immune suppressor cells such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) expand during disease progression or relapse and are reduced following TKI therapy. 77 , 80 Other immunological factors, such as dendritic cells (DCs), 83 plasmacytoid dendritic cells (pDCs), 84 CD8 + cytotoxic T-cells (CTLs), 85 leukemia-associated antigens (LAAs), 86 and B-cells, 87 also play a pivotal role in contributing to CML; however, further investigation should be launched to explore their impact on therapy responses. Additionally, studies have also indicated that imatinib and dasatinib treatment generates a more active immune system, and changes were not observed during bosutinib treatment.…”