Journal
ONCOTARGET
Volume 6, Issue 11, Pages 9612-9626Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3324
Keywords
myelodysplastic syndromes; hypomethylating agents; DNA methylation; programmed death-1; T cells
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Funding
- Rigshospitalets Research Foundation
- Novo Nordisk Foundation
- Danish Cancer Society
- Lundbeck Foundation [R180-2014-3675] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC0002209, NNF13OC0003435] Funding Source: researchfish
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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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