title: Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents.
abstract: Blockade of immune checkpoints is emerging as a new form of anticancer therapy. We studied the expression of programmed death ligand 1 (PD-L1), PD-L2, programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) mRNA in CD34+ cells from myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) patients (N=124). Aberrant upregulation (⩾2-fold) was observed in 34, 14, 15 and 8% of the patients. Increased expression of these four genes was also observed in peripheral blood mononuclear cells (PBMNCs) (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (P=0.018) and CMML (P=0.0128) compared with AML. By immunohistochemical analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared with patients who achieved response. Treatment of leukemia cells with decitabine resulted in a dose-dependent upregulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests that PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to hypomethylating agents. Blockade of this pathway can be a potential therapy in MDS and AML.
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bueso-Ramos
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: DiNardo
authors.affiliation: 1] Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA [2] Department of Molecular Carcinogenesis, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Estecio
authors.affiliation: Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Davanlou
authors.affiliation: 1] Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA [2] Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Q-R
authors.initials: QR
authors.lastname: Geng
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Stem Cell Transplantation, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parmar
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine