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

Abstract

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.

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

“…The modality features rapid plasma-membrane rupture and initiates the release of proinflammatory intracellular contents [16]. While pathogen-associated molecular patterns (PAMPs) and LPS are recognized by corresponding inflammasomes and caspases, such as caspase-1 (CASP1), caspase-3 (CASP3), caspase-11 (Casp11) and counterpart caspase-4 (CASP4), and caspase-5 (CASP5) in human, respectively to induce the activation of pyroptosis pathways, increasing evidence suggests that pyroptosis is deeply involved in infectious diseases [17], hematologic disorders [18], and tumorigenesis [19]. In addition, PAMPs and damage-associated molecular pattern (DAMPs)-induced activated inflammasomes are involved in the initiation of chronic inflammation and autoimmune diseases [17], which also initiate pyroptosis [20].…”

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

“…This exhausted phenotype can be reverted by the use of immune checkpoint blocking antibodies, such as anti-PD-1 therapy (i.e., nivolumab, pembrolizumab). Although preclinical studies suggested potential benefits of anti-PD-1 treatment, clinical trial outcomes after applying this treatment as a monotherapy are disappointing [ 104 ]. However, when combined with HMA, treatment with anti-PD-1 shows improvement in clinical response [ 104 ].…”

“…Although preclinical studies suggested potential benefits of anti-PD-1 treatment, clinical trial outcomes after applying this treatment as a monotherapy are disappointing [ 104 ]. However, when combined with HMA, treatment with anti-PD-1 shows improvement in clinical response [ 104 ].…”

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

“…Similarly, in oncohematology these ICIs have been used with limited success for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) [ 13 ]. PD-1 and PD-L1 both contribute to maintaining a strongly immunosuppressive tumor microenvironment, which favors the clonal evolution of blasts [ 14 ]. Insufficient clinical responses have been noted in patients with AML or myelodysplastic syndromes (MDSs) upon treatment with these ICIs [ 14 ].…”

“…PD-1 and PD-L1 both contribute to maintaining a strongly immunosuppressive tumor microenvironment, which favors the clonal evolution of blasts [ 14 ]. Insufficient clinical responses have been noted in patients with AML or myelodysplastic syndromes (MDSs) upon treatment with these ICIs [ 14 ].…”