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
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | OncoTarget |
Volume | 6 |
Issue number | 11 |
Pages (from-to) | 9612-26 |
Number of pages | 15 |
ISSN | 1949-2553 |
DOIs | |
Publication status | Published - 2015 |
- Aged, Aged, 80 and over, Antimetabolites, Azacitidine, Blood Cells, DNA Methylation, Drug Resistance, Female, Gene Expression Regulation, Humans, Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Chronic, Lymphocyte Activation, Male, Middle Aged, Myelodysplastic Syndromes, Neoplasm Proteins, Programmed Cell Death 1 Receptor, Promoter Regions, Genetic, RNA, Messenger, RNA, Neoplasm, T-Lymphocyte Subsets
Research areas
ID: 162677510