Activation of plasmacytoid dendritic cells promotes AML-cell fratricide
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Kavin Fatehchand1,2, Payal Mehta2, Christopher B. Colvin2, Nathaniel J. Buteyn2,4, Ramasamy Santhanam2, Giovanna Merchand-Reyes2,4, Hafza Inshaar2, Brenda Shen2, Xiaokui Mo3, Bethany Mundy-Bosse2, Susheela Tridandapani1,2 and Jonathan P. Butchar2
1 Medical Scientist Training Program, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
2 Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
3 Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
4 Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA
|Jonathan P. Butchar,||email:||email@example.com|
Keywords: plasmacytoid dendritic cells; interferon-beta; acute myeloid leukemia; fratricide
Abbreviations: pDC: plasmacytoid dendritic cell; AML: acute myeloid leukemia; IFNβ: Interferon-beta
Received: January 07, 2021 Accepted: April 06, 2021 Published: April 27, 2021
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 daratumumab-mediated 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.
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