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: H Yang, C Bueso-Ramos, C DiNardo, M R Estecio, M Davanlou, Q-R Geng, Z Fang, M Nguyen, S Pierce, Y Wei, S Parmar, J Cortes, H Kantarjian, G Garcia-Manero
• Journal: Leukemia (Leukemia) Vol. 28 Issue 6 Pg. 1280-8 (Jun 2014) ISSN: 1476-5551 [Electronic] England
• PMID: 24270737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• CTLA-4 Antigen
• CTLA4 protein, human
• PDCD1 protein, human
• PDCD1LG2 protein, human
• Programmed Cell Death 1 Ligand 2 Protein
• Programmed Cell Death 1 Receptor
• RNA, Messenger
• Decitabine
• Azacitidine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (pharmacology)
• Azacitidine (analogs & derivatives, pharmacology)
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor (genetics, metabolism)
• CTLA-4 Antigen (genetics, metabolism)
• Cohort Studies
• DNA Methylation
• Decitabine
• Female
• Flow Cytometry
• Humans
• Immunoenzyme Techniques
• Leukemia, Myeloid, Acute (drug therapy, genetics, mortality)
• Leukemia, Myelomonocytic, Chronic (drug therapy, genetics, mortality)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, genetics, mortality)
• Prognosis
• Programmed Cell Death 1 Ligand 2 Protein (genetics, metabolism)
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tumor Cells, Cultured