Hypomethylation and up-regulation ofPD-1in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation

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.

Epigenetic Modifiers in Immunotherapy: a Focus on Checkpoint Inhibitors

“…This was supported by another study demonstrating that azacitidine-mediated PD-1 promoter demethylation was associated with PD-1 mRNA upregulation and worse overall response in MDS patients. These findings suggest that PD-1 promoter demethylation correlates with poorer clinical response to azacitidine [44]. It has been shown that, during infection, the expression of PD-1 on T cells is regulated by DNA methylation [122].…”

“…Their application in cancer is limited by their modest clinical activity and relative toxicity [42] as single agents. Moreover, a majority of patients that benefit from HMAs will develop resistance due to unknown mechanism(s) [43,44]. Azacitidine is approved by the FDA for the treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia, and by the EMA for the treatment of acute myeloid leukemia (AML).…”

Treatment of Low-Blast Count AML using Hypomethylating Agents

“…Ørskov et al identified a correlation between PD-1 promoter demethylation and increased PD-1 expression in PB T-cells of patients with MDS, following consecutive cycles of AZA, that resulted into significantly worse ORR (8% vs. 60%, p = 0.014), and shorter OS (p = 0.11). A significantly higher baseline methylation level of the PD-1 promoter was observed in T-cells of non-responding patients also when compared to healthy controls (p = 0.023) 23. The HMT/ICI combination may increase treatment response due to demethylation and re-activation of genes related to interferon signaling, antigen presentation and inflammation, which may favour the activity of ICI 24…”

Hypomethylating agents after allogeneic blood stem cell transplantation

“…There are early preliminary signals from in-vitro and in-vivo systems suggesting that a combination of HMA and PD1-blocking agents may have a pathophysiological rationale in AML and MDS (51,52). Clinical trials investigating such approaches have just started in the non-transplant setting and, if successful, might be expanded to the field of relapse after allo-SCT.…”