Activation of plasmacytoid dendritic cells promotes AML-cell fratricide

Abstract

Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid blasts and a suppressed immune state. Interferons have been previously shown to aid in the clearance of AML cells. Type I interferons are produced primarily by plasmacytoid dendritic cells (pDCs). However, these cells exist in a quiescent state in AML. Because pDCs express TLR 7-9, we hypothesized that the TLR7/8 agonist R848 would be able to reprogram them toward a more active, IFN-producing phenotype. Consistent with this notion, we found that R848-treated pDCs from patients produced significantly elevated levels of IFNβ. In addition, they showed increased expression of the immune-stimulatory receptor CD40. We next tested whether IFNβ would influence antibody-mediated fratricide among AML cells, as our recent work showed that AML cells could undergo cell-to cell killing in the presence of the CD38 antibody daratumumab. We found that IFNβ treatment led to a significant, IRF9-dependent increase in CD38 expression and a subsequent increase in daratumumabmediated cytotoxicity and decreased colony formation. These findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed, and also demonstrate a possible means of enhancing endogenous Type I IFN production that would promote daratumumab-mediated clearance of AML cells.

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

“…The use of a TLR7/8 agonist leads to higher CD40 expression and an increase in INF-β production by pDC. Treatment with INF-β led to the upregulation of CD38 expression and a greater cytotoxicity of AML cells in the presence of daratumumab (anti-CD38 antibody) [ 73 ]. Another study about developing a dendritic cell vaccine to be used for therapy of minimal residual disease in acute myeloid leukemia assessed the uptake of apoptotic leukemic cells by monocyte-derived DC (MoDC) and DC after stimulating the TLR7/8 receptor.…”

Microenvironmental Features Driving Immune Evasion in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…Xiao et al showed a significant reduction of plasmacytoid dendritic cells (pDC) in AML patients, as well as blast: pDC ratio correlated with positive measurable residual disease and poor outcome [ 182 ]. On the contrary, elevated DC proportions of peripheral blood mononuclear cells have been reported accompanied by immunosuppressive characteristics [ 122 ], an effect reversed with a TLR7/8 agonist [ 183 , 184 ]. Additionally, tissue forming-pDC (TF-pDCs) positive patients had inferior prognosis [ 185 ].…”