S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are characterized by dysplastic and ineffective hematopoiesis that can result from aberrant expansion and activation of myeloid-derived suppressor cells (MDSCs) within the bone marrow (BM) niche. MDSCs produce S100A9, which mediates premature death of hematopoietic stem and progenitor cells (HSPCs). The PD-1/PD-L1 immune checkpoint impairs immune responses by inducing T-cell exhaustion and apoptosis, but its role in MDS is uncharacterized. Here we report an increased expression of PD-1 on HSPCs and PD-L1 on MDSCs in MDS versus healthy donors, and that this checkpoint is also activated in S100A9 transgenic (S100A9Tg) mice, and by treatment of BM mononuclear cells (BM-MNC) with S100A9. Further, MDS BM-MNC treated with recombinant PD-L1 underwent cell death, suggesting that the PD-1/PD-L1 interaction contributes to HSPC death in MDS. In accordance with this notion, PD-1/PD-L1 blockade restores effective hematopoiesis and improves colony-forming capacity in BM-MNC from MDS patients. Similar findings were observed in aged S100A9Tg mice. Finally, we demonstrate that c-Myc is required for S100A9-induced upregulation of PD-1/PD-L1, and that treatment of MDS HSPCs with anti-PD-1 antibody suppresses the expression of Myc target genes and increases the expression of hematopoietic pathway genes. We conclude anti-PD-1/anti-PD-L1 blocking strategies offer therapeutic promise in MDS in restoring effective hematopoiesis.

Immune checkpoints bone marrow expression as the predictor of clinical outcome in myelodysplastic syndrome

“…One of the promising groups of agents for MDS is checkpoint inhibitors, which has already revolutionized treatment landscape in other malignancies including melanoma, lung cancer, Hodgkin's disease and several others. The results of in vitro and animal studies indicate that early in MDS development inflammatory microenvironment is established in bone marrow [13] leading to pyroptosis of healthy hematopoietic progenitors, activation of myeloid-derived suppressor cells and specific cytokine milieu, which results in overexpression of checkpoint molecules including PD-1/PD-L1 [14] . Nevertheless, the trials of Nivolumab as single agent in MDS did not provide encouraging results [15] .…”

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

“…MDSCs express high levels of PD-L1 to restrain anti-tumour T-cell response. This upregulation of PD-L1 expression has been associated with the S100A9 inflammatory protein and HIF1α [167,188]. In addition, overexpression of PD-L1 has also been reported to induce aberrant hematopoiesis [188].…”

“…This upregulation of PD-L1 expression has been associated with the S100A9 inflammatory protein and HIF1α [167,188]. In addition, overexpression of PD-L1 has also been reported to induce aberrant hematopoiesis [188]. Another mechanism employed by MDSCs to suppress T-cell activity is through the recruitment of Tregs by the expression of immune stimulatory receptor CD40 on MDSCs [87].…”

The Role of S100A9 in the Interaction Between Pancreatic Ductal Adenocarcinoma Cells and Stromal Cells

“…High expression of PD-L1 in pancreatic cancers is associated with a poor prognosis [24]. According to published reports, S100A8 and S100A9 can induce the expression of PD-L1 in macrophages [28,47]. Therefore, we examined the effect of S100A9 on monocytes and found that S100A9 not only had chemotactic effects but could also induce surface expression of PD-L1 in monocytes.…”

“…In addition to its chemotactic effect, S100A9 has been reported to be the endogenous ligand of Toll-like receptor 4 (TLR4) and to induce surface expression of PD-L1 in primary hematopoietic cells [28,29]. High expression of PD-L1 in PDAC was associated with poor prognosis [30]; however, the mechanism that regulates the expression of PD-L1 in PDAC is not clear.…”