Development, function and clinical significance of plasmacytoid dendritic cells in chronic myeloid leukemia.
Abstract
Plasmacytoid dendritic cells (pDCs) are the main producers of a key T-cell stimulatory cytokine, interferon alpha (IFN) and critical regulators of anti-viral immunity. Chronic myeloid leukemia (CML) is caused by BCR-ABL, which is an oncogenic tyrosine kinase that can be effectively inhibited with ABL-selective kinase inhibitors (TKI). BCR-ABL-induced suppression of the transcription factor interferon regulatory factor 8 (IRF8) was previously proposed to block pDC development and compromise immune surveillance in CML. Here, we demonstrate that pDCs in newly diagnosed CML (CML-pDCs) develop quantitatively normal and are frequently positive for the co-stimulatory antigen CD86. They originate from low-level BCR-ABL-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 BCR-ABL-negative in MR, a substantial proportion of BCR-ABL+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 anti-leukemic immunity and treatment outcome in CML.