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Dendritic cells in myelodysplastic syndromes
stress. And, in the context of MDS it could lead to higher vulnerability for infections, which is often seen in this patient group. Altered TLR profiles have been observed in MDS CD34+ hematopoietic stem cells (HSC) before.16,63-66 Sustained TLR activation and constitutively activated downstream molecules as well as a loss of TLR signaling repressors have both been described in this context. Furthermore, enhanced TLR-mediated signaling in CD14+ MDS BM cells has been shown.67 It has been suggested that together this would lead to chronic immune stimula- tion and subsequent DNA damage and increased cell death. In contrast, it has been shown in AML that TLR stimulation of AML blasts with TLR agonists has a posi- tive effect and leads to differentiation.68 Thus, on one hand, increased TLR triggering can lead to excessive immune activation in hematopoietic progenitor cells, but on the other hand, decreased TLR function and defective down-stream signaling in immune effector cells (such as APC) can possibly lead to inadequate induction of immune responses and immune escape. This is important information for future studies that investigate the effect of therapeutic inhibition (by for example TLR antagonists) of these pathways in the complex MDS environment. Additionally, our gene expression data could form the basis for new research on expression levels of TLR on dif- ferent MDS-derived immune cells. These expression lev- els can be correlated to immune cell function and thera- peutic agents (e.g., TLR agonists/antagonists) should be tested in order to gain information on possible functional restoration of these cells.
DC primarily function as APC and for effective DC activity three signals are required for the interaction with T cells ( i) antigen presentation; ii) co-stimulation and iii) cytokine secretion). MDS BM- and NBM-derived APC were tested for their maturation, cytokine secretion and induction of T-cell priming capacity. cDC2 from MDS patients were able to upregulate HLA-DR and co-stimula- tory molecules to approximately the same extent as NBM cDC2. In contrast, slan+ monocytes showed impaired maturation capacity. For both subsets, the ability for cytokine secretion seemed largely unaffected. Although the capacity of upregulating co-stimulatory molecules and secreting cytokines was intact, cDC2 were unable to translate this into effective T-cell proliferation induction. Also cDC1 and slan+ monocytes showed a negatively affected T-cell stimulatory function. These results are part-
ly in line with previously published data on in vitro gener- ated MoDC from MDS patients.26,27,56,57 In these studies, MoDC were already affected in their maturation and cytokine secreting capacity, underlining the difference in naturally occurring DC and MoDC. Additionally, the effect of slan+ monocytes on T-cell polarization was assessed using mass cytometry. A clear induction of pro- inflammatory T cells (Th1 and Th17) as well as Tregs, combined with a considerable decrease in Th2 cells was observed in cultures with HD-derived slan+ monocytes. In contrast, cultures with MDS-derived slan+ monocytes showed similar Th1/Th17 skewing, but failed to expand Tregs and, above all, Th2 cells were induced, revealing altered T-effector cell induction. Thus, in addition to lower DC frequencies, we show altered functionality of MDS APC, which again can contribute to ineffective immune responses. Of note, there is high inter-patient variability and it would be highly interesting to correlate DC function with clinical parameters (e.g., molecular background, transfusion independence, better overall and leukemia-free survival) and frequencies of other immune cells by performing extensive immune profiling studies. Interestingly, Wang et al. have suggested an inhibitory role for MDS-derived mesenchymal stem cells (MSC) that may contribute to altered MoDC function.59 Whether this is also the case for different DC subsets has to be confirmed in future research.
In conclusion, this study provides the first data on the frequency and functionality of cDC subsets and slan+ monocytes in the context of MDS. It shows a clearly affected pro-inflammatory status of MDS-derived APC which might contribute to the complex process of immune escape. A more comprehensive insight in the basal immune-pathogenesis of this disease is essential for future studies that focus on new immunotherapeutic intervention options.
Disclosures
No conflicts of interest to disclose.
Contributions
NvL-K performed experiments; NvL-K, PP, GP and JT ana- lyzed data; NvL-K, TW, PP, GP, JT, SK, TdG, and AvdL inter- preted data;NvL-K, TW, SK, TdG, and AvdL designed research; PP performed FISH experiments; NvL-K, TW, SK, PP, TdG and AvdL wrote the paper.
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