Oncotarget

Clinical Research Papers:

Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation

Andreas D. Ørskov _, Marianne B. Treppendahl, Anni Skovbo, Mette S. Holm, Lone S. Friis, Marianne Hokland and Kirsten Grønbæk

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Oncotarget. 2015; 6:9612-9626. https://doi.org/10.18632/oncotarget.3324

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Abstract

Andreas D. Ørskov1,*, Marianne B. Treppendahl1,*, Anni Skovbo2,3, Mette S. Holm4, Lone S. Friis1,5, Marianne Hokland2, Kirsten Grønbæk1

1Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3FACS Core Facility, Aarhus University, Aarhus, Denmark

4Department of Hematology, Aarhus University Hospital, Aarhus, Denmark

5Department of Hematology, Odense University Hospital, Odense, Denmark

* These authors have contributed equally to this work.

Correspondence to:

Kirsten Grønbæk, e-mail: kirsten.groenbaek@regionh.dk

Keywords: myelodysplastic syndromes, hypomethylating agents, DNA methylation, programmed death-1, T cells

Received: November 29, 2014     Accepted: February 09, 2015     Published: March 18, 2015

ABSTRACT

The hypomethylating agents (HMAs) are standard therapy for patients with higher-risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023).

Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.


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