S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes
S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes
复制标题
DOI：
10.1038/s41375-019-0397-9
复制
发表时间：
2019-08-01
期刊：
影响因子：
11.4
通讯作者：
Wei, Sheng
中科院分区：
文献类型：
--
作者：
Cheng, Pinyang;Eksioglu, Erika A.;Wei, Sheng
骨髓增生异常综合征（MDS）的特征在于可由骨髓（BM）小生境内的髓源性抑制细胞（MDSC）的异常扩增和活化引起的发育异常和无效造血。MDSC产生S100 A9，其介导造血干细胞和祖细胞（HSPC）的过早死亡。PD-1/PD-L1免疫检查点通过诱导T细胞耗竭和细胞凋亡来损害免疫应答，但其在MDS中的作用尚不明确。在这里，我们报告了与健康供体相比，MDS中HSPC上的PD-1和MDSC上的PD-L1表达增加，并且该检查点在S100 A9转基因（S100 A9 Tg）小鼠中也被激活，并且通过用S100 A9处理BM单核细胞（BM-MNC）。此外，用重组PD-L1处理的MDS BM-MNC经历细胞死亡，表明PD-1/PD-L1相互作用有助于MDS中的HSPC死亡。根据这一观点，PD-1/PD-L1阻断剂恢复了MDS患者BM-MNC的有效造血并提高了集落形成能力。在老年S100 A9 Tg小鼠中观察到类似的结果。最后，我们证明了c-Myc是S100 A9诱导的PD-1/PD-L1上调所必需的，并且用抗PD-1抗体治疗MDS HSPC抑制了Myc靶基因的表达并增加了造血途径基因的表达。我们得出结论，抗PD-1/抗PD-L1阻断策略为MDS恢复有效造血提供了治疗前景。
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.