TY - JOUR

T1 - Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients

T2 - A rationale for combined targeting of PD-1 and DNA methylation

AU - Ørskov, Andreas D

AU - Treppendahl, Marianne B

AU - Skovbo, Anni

AU - Holm, Mette S

AU - Friis, Lone Smidstrup

AU - Hokland, Marianne

AU - Grønbæk, Kirsten

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Antimetabolites

KW - Azacitidine

KW - Blood Cells

KW - DNA Methylation

KW - Drug Resistance

KW - Female

KW - Gene Expression Regulation

KW - Humans

KW - Leukemia, Myeloid, Acute

KW - Leukemia, Myelomonocytic, Chronic

KW - Lymphocyte Activation

KW - Male

KW - Middle Aged

KW - Myelodysplastic Syndromes

KW - Neoplasm Proteins

KW - Programmed Cell Death 1 Receptor

KW - Promoter Regions, Genetic

KW - RNA, Messenger

KW - RNA, Neoplasm

KW - T-Lymphocyte Subsets

U2 - 10.18632/oncotarget.3324

DO - 10.18632/oncotarget.3324

M3 - Journal article

C2 - 25823822

VL - 6

SP - 9612

EP - 9626

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 11

ER -