Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function

Dhifaf Sarhan, Jinhua Wang, Upasana Sunil Arvindam, Caroline Hallstrom, Michael R. Verneris, Bartosz Grzywacz, Erica Warlick, Bruce R. Blazar, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Altered BM hematopoiesis and immune suppression are hallmarks of myelodysplastic syndrome (MDS). While the BM microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from patients with MDS (MDS-MSCs) compared with those from aged-matched normal controls for regulation of immune function. MDS-MSCs and healthy donor MSCs (HD-MSCs) exhibited a similar in vitro phenotype, and neither had a direct effect on NK cell function. However, when MDS- and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A MSC transcriptome was observed in MDS-MSCs compared with HD-MSCs, including increased expression of the ROS regulator, ENC1. High ENC1 expression in MDS-MSCs induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF-β superfamily of proteins. These monocytes also had reduced expression of the TGF-β transcriptional repressor MAB21L2, further adding to their immune-suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC-conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC-conditioned monocytes mimicked the MDS-MSC-suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune-suppressive microenvironment in MDS through an indirect mechanism involving monocytes.

Original languageEnglish (US)
Article numbere130155
JournalJCI Insight
Volume5
Issue number5
DOIs
StatePublished - Mar 12 2020

Bibliographical note

Funding Information:
We would like to thank the University of Minnesota Genomics Center and Juan E. Abrahante Lloréns for performing the whole genome sequencing and running the preliminary analysis. We would also like to thank Michelle Roesler for her efforts to identify MDS samples for this study. This work was supported by National Institutes of Health grants P01 CA65453 (to JSM and BRB), P01 CA111412 (to JSM), R35 CA197292 (to JSM), and R01 HL56067 (to BRB) and the Karolinska Institutet through a fellowship to DS.

Publisher Copyright:
© 2020, American Society for Clinical Investigation.

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