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Hematopoiesis
Reduced frequencies and functional impairment of dendritic cell subsets and non-classical monocytes in myelodysplastic syndromes
Nathalie van Leeuwen-Kerkhoff,1 Theresia M. Westers,1 Pino J. Poddighe,2 Giovanni A.M. Povoleri,3 Jessica A. Timms,4 Shahram Kordasti,4,5#
Tanja D. de Gruijl6# and Arjan A. van de Loosdrecht1#
1Department of Hematology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, the Netherlands; 2Department of Clinical Genetics, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, the Netherlands; 3Department Inflammation Biology, King's College London, Center for Inflammation Biology and Cancer Immunology, London, UK; 4Systems Cancer Immunology Lab, Comprehensive Cancer Center, King's College London, London, UK; 5Dipartimento Scienze Cliniche e Molecolari, UNIVPM, Ancona, Italy and 6Department of Medical Oncology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, the Netherlands
#SK, TDG and AAL contributed equally as co-senior authors.
ABSTRACT
In myelodysplastic syndromes (MDS) the immune system is involved in pathogenesis as well as in disease progression. Dendritic cells (DC) are key players of the immune system by serving as regulators of immune responses. Their function has been scarcely studied in MDS and most of the reported studies didn’t investigate naturally occurring DC subsets. Therefore, we here examined the frequency and function of DC subsets and slan+ non-classical monocytes in various MDS risk groups. Frequencies of DC as well as of slan+ monocytes were decreased in MDS bone marrow compared to normal bone marrow samples. Transcriptional profiling revealed down-regulation of transcripts related to pro-inflammatory pathways in MDS-derived cells as compared to nor- mal bone marrow. Additionally, their capacity to induce T-cell prolifera- tion was impaired. Multidimensional mass cytometry showed that whereas healthy donor-derived slan+ monocytes supported Th1/Th17/Treg differentiation/expansion their MDS-derived counter- parts also mediated substantial Th2 expansion. Our findings point to a role for an impaired ability of DC subsets to adequately respond to cel- lular stress and DNA damage in the immune escape and progression of MDS. As such, it paves the way toward potential novel immunothera- peutic interventions.
Introduction
Development of human dendritic cells (DC) occurs in the bone marrow (BM), where they originate from common precursor cells and differentiate into special- ized subsets: plasmacytoid DC (pDC) and conventional myeloid DC (cDC).1-3 These cDC are further separated in cDC1 (CD141+) and cDC2 (CD1c+) DC.4-6 Initially, a fourth DC subset, slanDC, was identified based on the expression of M-DC8 (6-sulfo LacNAc or slan) and CD16.7-9 Recent studies by our own group and others, showed that these cells are actually more closely related to monocytes than to DC and they were renamed slan+ non-classical monocytes.10-12 DC act as antigen presenting cells (APC) and orchestrate immune responses. Upon activa- tion DC undergo a maturation process and up-regulate co-stimulatory molecules and secrete different types of cytokines, leading to antigen presentation and sub- sequent cellular immune responses.13 In several hematological malignancies immune dysregulation affecting the DC compartment has been reported, which
Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):655-667
Correspondence:
ARJAN A. VAN DE LOOSDRECHT
a.vandeloosdrecht@amsterdamumc.nl
Received: July 26, 2020. Accepted: February 3, 2021. Pre-published: February 11, 2021.
https://doi.org/10.3324/haematol.2020.268136 ©2022 Ferrata Storti Foundation
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