Page 127 - Haematologica April 2020

TM+ monocytes in myelodysplastic syndromes
Discussion
The BM microenvironment in MDS, and particularly in low-risk groups, is often characterized by the presence of pro-inflammatory cells and molecules. While increased inflammation and the subsequent cellular immune response are crucial to eliminate malignant cells, continu- ous immune stimulation could lead to genomic instability and inevitable malignant transformation.12 Identifying the factors that could maintain a healthy overall immune response in MDS is important and clinically relevant. In mice, it has been shown that lack of the lectin-like domain of TM leads to reduced survival after exposure to endo- toxins, whereas a recombinant form diminished NF-κB and MAPK activation.45 In the current study, we therefore investigated the presence of TM on immune cells in MDS- derived BM and PB samples and its immune-modulatory role in MDS. TM was mainly expressed on monocyte sub- sets and not on granulocytes, lymphocytes or eosinophils. The difference in TM expression between monocytes from healthy donors and those from patients with MDS was most evident for classical monocytes. FISH analysis showed clonal involvement for these TM+ monocytes. This subset showed hardly any TM expression on cells derived from either healthy BM or healthy PB. In MDS patients there was marked variation in monocytes expressing TM. Some patients showed expression levels similar to those on healthy donor-derived monocytes, whereas for others nearly all monocytes expressed TM. We found that the percentage of TM expression was clear- ly higher in low-risk MDS groups than in higher-risk groups, suggesting that the presence of TM may be prima- rily observed in a pro-inflammatory environment (i.e. low-risk MDS). Interestingly, Talati et al. previously described a correlation between the presence of classical monocytosis in MDS and favorable prognostic factors such as increased white blood cell counts and absolute neutrophil counts.46 Furthermore, an increased percentage of monocytes was associated with lower MDS risk groups and good-risk cytogenetics. SF3B1 was present at a higher frequency in this MDS group and overall survival of these patients tended to be better. In this perspective, it would
be interesting to investigate the presence of TM in a same set of samples in future research.
Besides active secretion and passive release of inflam- matory molecules in the MDS BM environment, certain T- cell subsets, particularly Th1 and Th17 type T cells, con- tribute to an immune-active state by the secretion of high amounts of interferon-γ and interleukin-17. In order to investigate the effect of monocytes on T-cell skewing, healthy T cells were cultured in the presence of TM+ or TM- MDS monocytes. Using mass cytometry, we were able to utilize a comprehensive panel of surface and intra- cellular markers for this purpose. Interestingly, T cells cul- tured in the presence of TM+ monocytes showed an anti- inflammatory skewed profile. Compared to T cells cul- tured with TM- monocytes, they showed less interferon-γ positivity and higher concentrations of interleukin-4 and interleukin-10 measured intracellularly. While the number of patients’ samples was limited and data need to be inter- preted with caution, our findings suggest that TM+ mono- cytes polarize T cells toward Th2 and/or Treg phenotypes.
Collectively, our data point to an interesting function for TM-expressing monocytes in the highly inflammatory environment of low-risk MDS patients. They could play an essential role in dampening disproportionate immune activation by inducing anti-inflammatory T-cell subsets. In keeping with this notion, overall and leukemia-free sur- vival was better for patients in whom the BM contained TM+ monocytes than for patients lacking TM expression, supporting a clinically relevant mechanism. Nevertheless, in the longer term, this mechanism could lead to a pro- found immunosuppressive state which would prevent effective immune surveillance; a common condition in higher-risk MDS.
Acknowledgments
We thank M.G.H.P. Raaijmakers for a critical review of our manuscript. Furthermore, we acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre awarded to Guy’s & St Thomas’ NHS Foundation Trust in Partnership with King’s College London and King’s College Hospital NHS Foundation Trust.
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