[HTML][HTML] 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

AD Ørskov, MB Treppendahl, A Skovbo, MS Holm… - Oncotarget, 2015 - ncbi.nlm.nih.gov
AD Ørskov, MB Treppendahl, A Skovbo, MS Holm, LS Friis, M Hokland, K Grønbæk
Oncotarget, 2015ncbi.nlm.nih.gov
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 …
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).
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