Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents

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

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292 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1280-1288
Number of pages9
JournalLeukemia
Volume28
Issue number6
DOIs
StatePublished - Jun 2014
Externally publishedYes

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Keywords

  • DNA methylation
  • myelodysplastic syndromes
  • programmed death-1

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Yang, H., Bueso-Ramos, C., Dinardo, C., Estecio, M. R., Davanlou, M., Geng, Q. R., Fang, Z., Nguyen, M., Pierce, S., Wei, Y., Parmar, S., Cortes, J., Kantarjian, H., & Garcia-Manero, G. (2014). Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia, 28(6), 1280-1288. https://doi.org/10.1038/leu.2013.355