Activation of plasmacytoid dendritic cells promotes AML-cell fratricide
Open Access
- 27 April 2021
- journal article
- Published by Impact Journals, LLC in Oncotarget
- Vol. 12 (9), 878-890
- https://doi.org/10.18632/oncotarget.27949
Abstract
// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> 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 Correspondence to: Jonathan P. Butchar, email: butchar.2@osu.edu Susheela Tridandapani, email: tridandapani.2@osu.edu 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 Copyright: © 2021 Fatehchand et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 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.Keywords
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