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

• Published in: Leukemia 2019-08, Vol.33 (8), p.2034-2046
• Main Authors: Cheng, Pinyang, Eksioglu, Erika A., Chen, Xianghong, Kandell, Wendy, Le Trinh, Thu, Cen, Ling, Qi, Jin, Sallman, David A., Zhang, Yu, Tu, Nhan, Adams, William A., Zhang, Chunze, Liu, Jinhong, Cleveland, John L., List, Alan F., Wei, Sheng
• Format: Article
• Language: English
• Subjects: 13/2; 13/31; 13/95; 64/110; 64/60; 692/699/1541/13; 692/699/1541/1990/1673; 82/1; 82/29; 82/80; Animals; Antibodies; Apoptosis; B7-H1 Antigen - analysis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - physiology; Bone marrow; c-Myc protein; Calgranulin B - physiology; Cancer Research; Care and treatment; Cell activation; Cell death; Cells (biology); Critical Care Medicine; Disorders; Exhaustion; Gene expression; Genes; Genetic aspects; Health aspects; Hematology; Hematopoiesis; Hematopoietic stem cells; Humans; Immune checkpoint; Immune response; Intensive; Internal Medicine; Leukocytes (mononuclear); Lymphocytes T; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mortality; Myc protein; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - etiology; Oncology; PD-1 protein; PD-L1 protein; Progenitor cells; Programmed Cell Death 1 Receptor - analysis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - physiology; Proto-Oncogene Proteins c-myc - physiology; Risk factors; Suppressor cells; T cells; Transgenic mice
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0397-9

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.