Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming

Jiazhu Wu, Xiaojing Xu, Eun Joon Lee, Austin Y. Shull, Lirong Pei, Farrukh Awan, Xiaoling Wang, Jeong-Hyeon Choi, Libin Deng, Hong Bo Xin, Wenxun Zhong, Jinhua Liang, Yi Miao, Yujie Wu, Lei Fan, Jianyong Li, Wei Xu, Huidong Shi

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)40558-40570
Number of pages13
JournalOncotarget
Volume7
Issue number26
DOIs
StatePublished - Jan 1 2016

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T-Cell Prolymphocytic Leukemia
Epigenomics
B-Cell Chronic Lymphocytic Leukemia
T-Lymphocytes
DNA Methylation
Immunosuppression
Programmed Cell Death 1 Receptor
Tissue Donors
CD4-CD8 Ratio
Immunosuppressive Agents
Luciferases
Genes
Interleukin-2
Anti-Idiotypic Antibodies
Genome
Phenotype
Survival

Keywords

  • CD8 T-cells
  • Chronic lymphocytic leukemia
  • DNA methylation
  • PD-1

ASJC Scopus subject areas

  • Oncology

Cite this

Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming. / Wu, Jiazhu; Xu, Xiaojing; Lee, Eun Joon; Shull, Austin Y.; Pei, Lirong; Awan, Farrukh; Wang, Xiaoling; Choi, Jeong-Hyeon; Deng, Libin; Xin, Hong Bo; Zhong, Wenxun; Liang, Jinhua; Miao, Yi; Wu, Yujie; Fan, Lei; Li, Jianyong; Xu, Wei; Shi, Huidong.

In: Oncotarget, Vol. 7, No. 26, 01.01.2016, p. 40558-40570.

Research output: Contribution to journalArticle

Wu, J, Xu, X, Lee, EJ, Shull, AY, Pei, L, Awan, F, Wang, X, Choi, J-H, Deng, L, Xin, HB, Zhong, W, Liang, J, Miao, Y, Wu, Y, Fan, L, Li, J, Xu, W & Shi, H 2016, 'Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming', Oncotarget, vol. 7, no. 26, pp. 40558-40570. https://doi.org/10.18632/oncotarget.9941
Wu, Jiazhu ; Xu, Xiaojing ; Lee, Eun Joon ; Shull, Austin Y. ; Pei, Lirong ; Awan, Farrukh ; Wang, Xiaoling ; Choi, Jeong-Hyeon ; Deng, Libin ; Xin, Hong Bo ; Zhong, Wenxun ; Liang, Jinhua ; Miao, Yi ; Wu, Yujie ; Fan, Lei ; Li, Jianyong ; Xu, Wei ; Shi, Huidong. / Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming. In: Oncotarget. 2016 ; Vol. 7, No. 26. pp. 40558-40570.
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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 na{\"i}ve 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.",
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AU - Pei, Lirong

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AU - Choi, Jeong-Hyeon

AU - Deng, Libin

AU - Xin, Hong Bo

AU - Zhong, Wenxun

AU - Liang, Jinhua

AU - Miao, Yi

AU - Wu, Yujie

AU - Fan, Lei

AU - Li, Jianyong

AU - Xu, Wei

AU - Shi, Huidong

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N2 - 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.

AB - 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.

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