Abstract
Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.
Highlights
Chronic lymphocytic leukemia (CLL), the most common type of adult leukemia in the western world, is characterized by the progressive accumulation of monoclonal B cells
It has been shown that the numbers of CD4+ and CD8+ T cells are associated with prognosis in chronic lymphocytic leukemia (CLL) [18, 19]
The median number of CD8+ T cells in this cohort was 0.80 × 109 cells/L, while the median number of CD4+ T cells was 1.12 × 109 cells/L. 54 patients (23.1%) showed an inversion in the CD4/CD8 ratio based on a cutoff ratio of 1.0, indicating the CD8+ T-cell subset is larger than the CD4+ subset in this subgroup of CLL patients (Figures 1A– 1C)
Summary
Chronic lymphocytic leukemia (CLL), the most common type of adult leukemia in the western world, is characterized by the progressive accumulation of monoclonal B cells. T cells from the Eμ-TCL1 transgenic CLL mouse model exhibit similar gene expression profiles and functional defects as those seen in CLL patients [8, 9]. The study demonstrated that PD-1 up-regulation coincided with demethylation of the PD-1 cis-regulatory region, and this demethylated state was maintained as a result of chronic antigen stimulation [17]. Based on these observations, we hypothesize that similar epigenetic alterations are involved in T-cell dysfunction within CLL patients. Our results suggest that the exhaustion phenotype observed in CLL CD8+ T cells is associated with altered DNA methylation profiles in immune regulatory genes
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