Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

Abstract

Plasmacytoid dendritic cells (pDC) are the main type I interferon producing cells in humans and are able to modulate innate and adaptive immune responses. Tumor infiltration by plasmacytoid dendritic cells is already well described and is associated with poor outcomes in cancers due to the tolerogenic activity of pDC. In hematological diseases, Blastic Plasmacytoid Dendritic Cells Neoplasm (BPDCN), aggressive leukemia derived from pDCs, is well described, but little is known about tumor infiltration by mature pDC described in Myeloid Neoplasms (MN). Recently, mature pDC proliferation (MPDCP) has been described as a differential diagnosis of BPDCN associated with acute myeloid leukemia (pDC-AML), myelodysplastic syndrome (pDC-MDS) and chronic myelomonocytic leukemia (pDC-CMML). Tumor cells are myeloid blasts and/or mature myeloid cells from related myeloid disorders and pDC derived from a clonal proliferation. The poor prognosis associated with MPDCP requires a better understanding of pDC biology, MN oncogenesis and immune response. This review provides a comprehensive overview about the biological aspects of pDCs, the description of pDC proliferation in MN, and an insight into putative therapies in pDC-AML regarding personalized medicine.

Keywords: acute myeloid leukemia; blastic plasmacytoid dendritic cells neoplasm; mature plasmacytoid dendritic cells proliferation; plasmacytoid dendritic cells; tumor microenvironment.

Figure 1

Plasmacytoid dendritic cell (pDC) development and functions. During development and activation of pDC, several networks are successively involved as specification program, differentiation program, innate and adaptive response pathways, and regulatory pathways. Specification program of pDC start in progenitors through PU.1 expression, FLT3 and TCF4 pathway leading to IRF8 activation. Differentiation into pDC depends to SPIB expression leading to IRF7, IRF8 and IRF5 activation, IFN-I (IFNα, IFNβ, IFNω) and IFN-III (IFNλ) secretion, and expression of several genes involved in pDC functions. Innate response develops from pattern recognition receptors (PPRs) such as Toll-like receptors (TLR), NOD-like receptors (NLRs), cytosolic DNA sensors (CDCs) and receptor for advanced glycation end products (RAGE) leading to IFN-I secretion, cytokines and chemokines secretion, and proteins expression involved in adaptive response. After activation and molecule of histocompatibility complex (MHC) class II antigen presentation, pDCs express several immune checkpoint molecules. Other regulatory molecules are expressed by pDC after IFN-I and cytokines production. Specific markers were reported in Blastic pDC Neoplasm (BPDCN, purple background), Mature pDC Proliferation (MPDCP, pink), and solid cancers (salmon red) including mutations (star) and overexpression (underline).