Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.