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Myelodysplasias

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

Leukemia volume 28, pages 1280–1288 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by the Ruth and Ken Arnold Leukemia Fund, the Edward P Evans Foundation, the DoD Peer Review Cancer Research Program (PRCRP) Discovery Award CA110791, the generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program and the MD Anderson Cancer Center Support Grant (CCSG) CA016672. We thank Michael Fernandez for technical help.

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Authors and Affiliations

  1. Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA

    H Yang, C DiNardo, M R Estecio, Q-R Geng, Z Fang, S Pierce, Y Wei, J Cortes, H Kantarjian & G Garcia-Manero

  2. Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX, USA

    C Bueso-Ramos, M Davanlou & M Nguyen

  3. Department of Molecular Carcinogenesis, University of Texas MD Cancer Center, Houston, TX, USA

    M R Estecio

  4. Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Q-R Geng

  5. Department of Stem Cell Transplantation, University of Texas MD Cancer Center, Houston, TX, USA

    S Parmar

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Correspondence to G Garcia-Manero.

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Yang, H., Bueso-Ramos, C., DiNardo, C. et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28, 1280–1288 (2014). https://doi.org/10.1038/leu.2013.355

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