title: Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation.
abstract: The hypomethylating agents (HMAs) are standard therapy for patients with higher-risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023). Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Ørskov
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Treppendahl
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|FACS Core Facility, Aarhus University, Aarhus, Denmark.
authors.forename: Anni
authors.initials: A
authors.lastname: Skovbo
authors.affiliation: Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mette S
authors.initials: MS
authors.lastname: Holm
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.|Department of Hematology, Odense University Hospital, Odense, Denmark.
authors.forename: Lone S
authors.initials: LS
authors.lastname: Friis
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hokland
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbæk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000963:Antimetabolites / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004351:Drug Resistance; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000963:Antimetabolites; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D001374:Azacitidine
keywords: DNA methylation; T cells; hypomethylating agents; myelodysplastic syndromes; programmed death-1
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