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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.

Ørskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M, Grønbæk K - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

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.

No MeSH data available.


Related in: MedlinePlus

Dynamics of PD-1 promoter methylation in peripheral blood CD4+ and CD8+ T cells from patients without PD-1 promoter demethylation during treatment with 5-azacytidine(A)PD-1 promoter methylation in CD4+ T cells of 14 patients. (B)PD-1 promoter methylation in CD8+ T cells of 14 patients. In patient no. 123 we observed demethylation in the CD4+ T cells (CD4+ T cells from patient no. 123 are included in Figure 3A) and in patient no. 60 we observed demethylation in the CD8+ T cells (CD8+ T cells from patient no. 60 are included in Figure 3A). C = course of 5-aza treatment. D = day in treatment course.
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Figure 4: Dynamics of PD-1 promoter methylation in peripheral blood CD4+ and CD8+ T cells from patients without PD-1 promoter demethylation during treatment with 5-azacytidine(A)PD-1 promoter methylation in CD4+ T cells of 14 patients. (B)PD-1 promoter methylation in CD8+ T cells of 14 patients. In patient no. 123 we observed demethylation in the CD4+ T cells (CD4+ T cells from patient no. 123 are included in Figure 3A) and in patient no. 60 we observed demethylation in the CD8+ T cells (CD8+ T cells from patient no. 60 are included in Figure 3A). C = course of 5-aza treatment. D = day in treatment course.

Mentions: The 22 patients had received a median number of five courses of 5-aza (range 3–14). A total of 132 PB samples were sorted and analyzed. Nine (41%) of the patients demonstrated a significant decrease in PD-1 promoter methylation in the T cell compartment after 5-aza administration (Figure 3A and 3B). In two of these patients we only observed demethylation in either the CD4+ T cells or the CD8+ T cells. In the remaining 13 patients an increase in PD-1 methylation or no methylation changes were observed (Figure 4A and 4B). The mean baseline methylation level in T cells was significantly higher in the group of patients in whom we observed a demethylation of the PD-1 promoter, both compared to patients where no demethylation were observed (48.0% (SD 15.8) vs. 25.7% (SD 9.4) (p < .001, 95%-CI [13.1;31.5]), and compared to healthy donors (48.0% (SD 15.8) vs. 24.5% (SD 11.1) (p < .0001, 95%-CI [11.7;35.4])) (Figure 5). A trend towards higher PD-1 baseline methylation in the patients' PBMNCs and T cells compared to those of healthy donors was observed (PBMNCs, p = 0.07; 95%-CI [−1.7;38.2], T cells, p = 0.16; 95%-CI [−3.0;17.7]).


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.

Ørskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M, Grønbæk K - Oncotarget (2015)

Dynamics of PD-1 promoter methylation in peripheral blood CD4+ and CD8+ T cells from patients without PD-1 promoter demethylation during treatment with 5-azacytidine(A)PD-1 promoter methylation in CD4+ T cells of 14 patients. (B)PD-1 promoter methylation in CD8+ T cells of 14 patients. In patient no. 123 we observed demethylation in the CD4+ T cells (CD4+ T cells from patient no. 123 are included in Figure 3A) and in patient no. 60 we observed demethylation in the CD8+ T cells (CD8+ T cells from patient no. 60 are included in Figure 3A). C = course of 5-aza treatment. D = day in treatment course.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496243&req=5

Figure 4: Dynamics of PD-1 promoter methylation in peripheral blood CD4+ and CD8+ T cells from patients without PD-1 promoter demethylation during treatment with 5-azacytidine(A)PD-1 promoter methylation in CD4+ T cells of 14 patients. (B)PD-1 promoter methylation in CD8+ T cells of 14 patients. In patient no. 123 we observed demethylation in the CD4+ T cells (CD4+ T cells from patient no. 123 are included in Figure 3A) and in patient no. 60 we observed demethylation in the CD8+ T cells (CD8+ T cells from patient no. 60 are included in Figure 3A). C = course of 5-aza treatment. D = day in treatment course.
Mentions: The 22 patients had received a median number of five courses of 5-aza (range 3–14). A total of 132 PB samples were sorted and analyzed. Nine (41%) of the patients demonstrated a significant decrease in PD-1 promoter methylation in the T cell compartment after 5-aza administration (Figure 3A and 3B). In two of these patients we only observed demethylation in either the CD4+ T cells or the CD8+ T cells. In the remaining 13 patients an increase in PD-1 methylation or no methylation changes were observed (Figure 4A and 4B). The mean baseline methylation level in T cells was significantly higher in the group of patients in whom we observed a demethylation of the PD-1 promoter, both compared to patients where no demethylation were observed (48.0% (SD 15.8) vs. 25.7% (SD 9.4) (p < .001, 95%-CI [13.1;31.5]), and compared to healthy donors (48.0% (SD 15.8) vs. 24.5% (SD 11.1) (p < .0001, 95%-CI [11.7;35.4])) (Figure 5). A trend towards higher PD-1 baseline methylation in the patients' PBMNCs and T cells compared to those of healthy donors was observed (PBMNCs, p = 0.07; 95%-CI [−1.7;38.2], T cells, p = 0.16; 95%-CI [−3.0;17.7]).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

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.

No MeSH data available.


Related in: MedlinePlus