Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents

Abstract

Blockade of immune checkpoints is emerging as new form of anticancer therapy. We studied the expression of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in CD34+ cells from MDS, CMML and AML patients (N=124). Aberrant up-regulation (≥2 fold) was observed in 34%, 14%, 15% and 8% of the patients respectively. Increased expression of these 4 genes was also observed in PBMNC (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (p=0.018) and CMML (p=0.0128) compared to AML. By immunohistochemical (IHC) analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared to patients that achieved response. Treatment of leukemia cells with decitabine resulted in a dose dependent up-regulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to HMAs. Blockade of this pathway can be a potential therapy in MDS and AML.

5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft

“…22 Given the overall disappointing outcome of patients presenting with more aggressive relapse in the initial cohort of 26 patients, we had in 2009 markedly increased the initial 5-azacytidine dosing on the basis of several features of disease dynamics, including excess peripheral blood blasts. Nonetheless, of the 18 patients now analyzed who had received 100 mg/m 2 on 5 days, only 1 patient achieved a CR and the rate of temporary disease control was only 18% (3 patients), thus still far below the outcome in patients without these features, who had received the 3-day treatment.…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…Finally, there are early preliminary signals from in vitro and in vivo analyses suggesting that a combination of HMA and PD1-blocking agents may have a pathophysiological rationale in AML and MDS [78,79]. Along with this, first reports suggest that immune checkpoint blockade may also be efficient in case of relapse after allo-SCT [80,81].…”

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

“…Pharmacologically induced gene methylation, however, has been shown to adjust PD-L1 expression in various malignancies. 11 In prostate cancer and acute myeloid leukemia cohorts analyzed by The Cancer Genome Atlas (TCGA), CD274 promoter methylation (mPD-L1) correlates with gene expression and is associated with survival. 12,13 We therefore hypothesized that PD-L1 expression might be under direct epigenetic control in CRC as well and consequently might be of major importance for the stratification of patients potentially benefitting from immunotherapeutic PD-1/PD-L1 checkpoint inhibition.…”