Collectively, these findings (1) expand our understanding of the role of PD-1/PD-L1 interaction beyond T cells, which has implications for general immunology and immunotherapy; (2) demonstrate that S100A9, which is instrumental in the pathogenesis of MDS, plays a critical role in the induction of PD-1/PD-L1 surface receptor expression on HSPCs and MDSCs; and (3) suggest that PD-1/PD-L1 signaling contributes to ineffective hematopoiesis in MDS. Here, CD274 is linked to myelodysplastic syndrome.