Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming
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Jiazhu Wu1,2,3, Xiaojing Xu4, Eun-Joon Lee3, Austin Y. Shull3,5, Lirong Pei3, Farrukh Awan6, Xiaoling Wang4, Jeong-Hyeon Choi3, Libin Deng7, Hong-Bo Xin7, Wenxun Zhong8, Jinhua Liang1,2, Yi Miao1,2, Yujie Wu1,2, Lei Fan1,2, Jianyong Li1,2, Wei Xu1,2, Huidong Shi3,5
1Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu, 210029, China
2Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210029, China
3Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
4Georgia Prevention Institute, Augusta University, Augusta, GA 30912, USA
5Department of Biochemistry & Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
6Division of Hematology, The Ohio State University, Columbus, OH, 43210, USA
7Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
8Department of Statistics, University of Georgia, Athens, GA 30602, USA
Wei Xu, email: email@example.com
Huidong Shi, email: firstname.lastname@example.org
Keywords: chronic lymphocytic leukemia, DNA methylation, CD8+ T-cells, PD-1
Received: December 05, 2015 Accepted: May 13, 2016 Published: June 10, 2016
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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