Page 119 - Haematologica April 2020

Myelodysplastic Syndrome
Thrombomodulin-expressing monocytes are associated with low-risk features in myelodysplastic syndromes and dampen excessive immune activation
Nathalie van Leeuwen-Kerkhoff,1 Theresia M. Westers,1 Pino J. Poddighe,2 Tanja D. de Gruijl,3* Shahram Kordasti4* and Arjan A. van de Loosdrecht1*
1Department of Hematology, Amsterdam UMC, Cancer Center Amsterdam, the Netherlands; 2Department of Clinical Genetics, Amsterdam UMC, Amsterdam, the Netherlands; 3Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, the Netherlands and 4Comprehensive Cancer Center, King's College London and Guy’s Hospital, London, UK
*TDdG, SK and AAvdL contributed equally to this work.
ABSTRACT
The bone marrow of patients with low-risk myelodysplastic syn- dromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response generally contributes to antitumor responses and may prevent disease pro- gression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an impor- tant aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and desta- bilizing inflammation in lower-risk disease. In this study we investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of MDS patients in different risk groups. Patient-derived classical monocytes showed high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombo- modulin. The presence of thrombomodulin on monocytes from MDS patients correlated with lower-risk disease groups and better overall and leukemia-free survival. Using multidimensional mass cytometry, in an in- vitro setting, we showed that thrombomodulin-positive monocytes could polarize naïve T cells toward cell clusters which are closer to T helper type 2 and T regulatory cell phenotypes and less likely to contribute to effective immune surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low-risk MDS and may represent a new mechanism in the protection against disproportionate immune activation.
Introduction
The immune system plays an important role in the pathogenesis and disease course of myelodysplastic syndromes (MDS). The immune status can be markedly different between MDS prognostic risk groups. Low-risk disease is often character- ized by an increased number and activation state of pro-inflammatory immune cells [i.e. T helper (Th)17, natural killer (NK) and CD8+ cytotoxic T cells1–6] whereas in high-risk disease an immunosuppressive response is the dominant feature [i.e. expansion of T regulatory cells (Treg)7–10 and myeloid-derived suppressor cells11] which could facilitate immune escape and eventually progression to acute myeloid leukemia. Although an “activated” immune system and associated tumor-specific immune responses are crucial for effective immune surveillance and elimination of the malignant clone, in the longer term chronic immune stimulation may enhance the risk of genomic instability and development of MDS/acute myeloid leukemia.12 Smoldering inflammation as a result of aberrant activation of inflammatory path-
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):961-971
Correspondence:
ARJAN A. VAN DE LOOSDRECHT
a.vandeloosdrecht@vumc.nl
Received: February 12, 2019. Accepted: July 2, 2019. Pre-published: July 4, 2019.
doi:10.3324/haematol.2019.219303
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/961
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