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PD-L1 (CD274) promoter methylation predicts survival in patients with acute myeloid leukemia

Leukemia volume 31, pages 738–743 (2017)Cite this article

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In adult patients with acute myeloid leukemia (AML), short-term complete remission is achieved with standard chemotherapy in the majority of cases. Long-term remission, however, is attained in <50% of patients with established treatment protocols.1 Targeting the immune system as novel therapeutic modality has proven efficacy in several settings and treatments targeting immune checkpoint molecules, especially programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), may foster innate immune responses antagonizing tumor growth.2 T-cell suppression preventing excessive inflammatory response at the site of chronic inflammation depends on an intact PD-1/PD-L1 axis.3 In the presence of activated T cells, in return, AML cells upregulate PD-L1/PD-L2, the major mediators of immunosuppression, resulting in inhibition of Thelper cell response and ‘T-cell exhaustion’ via the PD-1 pathway.4 Experimental studies have revealed that the PD-L1/PD-1 pathway contributes to tumor dormancy and long-term persistence in AML.5

Hypomethylating 5-azacytidine (5-aza) has been shown to improve overall survival (OS) in subgroups of AML patients.6 Recently, 5-aza has been reported to induce PD-1 expression on T cells in the microenvironment of AML.7 Analogously, in nine AML patients treated with epigenetic therapy using demethylating decitabine, PD-L1/PD-L2, PD-1 and CTLA4 expression was upregulated in a dose-dependent manner.8 To date, data on the regulation of the extended PD-1/PD-L1 axis on an epigenetic level are sparse, and promoter methylation of CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2) in particular has not yet been described as an associated mechanism.9 For PDCD1 (encoding PD-1) and CTLA4, on the other hand, epigenetic regulation is described in lymphocytes.10, 11 On the basis of Yang et al.,8 we hypothesized that PD-L1/PD-L2 expression may be under direct control of epigenetic modulation in AML and may be of major importance for the stratification of patients potentially benefitting from PD-1 checkpoint inhibition. In the following, our main focus will be on CD274/PDCD1LG2 (PD-L1/PD-L2). For the sake of completeness, however, analyses of PDCD1 and CTLA4 were included and specified in Table 1.

Table 1 Patients’ characteristics of 197 AML patients from The Cancer Genome Atlas
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Author notes

  1. D Goltz and H Gevensleben: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Pathology, University Hospital Bonn, Bonn, Germany

    D Goltz, H Gevensleben, S Grünen, G Kristiansen & D Dietrich

  2. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany

    J Dietrich & D Dietrich

  3. Department of Dermatology, University Hospital Bonn, Bonn, Germany

    J Landsberg

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Correspondence to D Dietrich.

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Competing interests

DD has been an employee and is a stockholder of Epigenomics AG. DD is inventor and co-inventor and owns patents on methylation biomarkers and related technologies. DD receives inventor’s compensation from Epigenomics AG. DD is a consultant for AJ Innuscreen GmbH (Berlin, Germany) and receives royalties from product sales. DD is a consultant and receives or received compensation from Therawis GmbH (Munich, Germany), Oncgnostics GmbH (Jena, Germany), MDxHealth, Inc. (Irvine, CA, USA), Epigenomics AG (Berlin, Germany) and R-Biopharm AG (Darmstadt, Germany). A patent on methylation of immune checkpoint genes (incl. CD274, PDCD1, PDCD1LG2, and CTLA4) as predictive and prognostic biomarkers is pending (inventor: Dimo Dietrich). The remaining authors declare no conflict of interest.

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Goltz, D., Gevensleben, H., Grünen, S. et al. PD-L1 (CD274) promoter methylation predicts survival in patients with acute myeloid leukemia. Leukemia 31, 738–743 (2017). https://doi.org/10.1038/leu.2016.328

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