Research Papers:

Genome wide DNA methylation landscape reveals glioblastoma’s influence on epigenetic changes in tumor infiltrating CD4+ T cells

Marpe Bam, Sreenivasulu Chintala, Kaleigh Fetcko, Brooke Carmen Williamsen, Seema Siraj, Sheng Liu, Jun Wan, Xiaoling Xuei, Yunlong Liu, Adam T. Leibold and Mahua Dey _

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Oncotarget. 2021; 12:967-981. https://doi.org/10.18632/oncotarget.27955

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Marpe Bam1,*, Sreenivasulu Chintala2,*, Kaleigh Fetcko2, Brooke Carmen Williamsen1, Seema Siraj1, Sheng Liu3, Jun Wan3, Xiaoling Xuei3, Yunlong Liu3, Adam T. Leibold2 and Mahua Dey1,2

1 Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

2 Department of Neurosurgery, Indiana University School of Medicine, Indianapolis, IN, USA

3 Department of Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA

* These authors contributed equally to this work

Correspondence to:

Mahua Dey,email: [email protected]

Keywords: glioblastoma; malignant glioma; CD4+ T cell; DNA methylation; brain cancer

Received: April 05, 2021     Accepted: April 19, 2021     Published: May 11, 2021

Copyright: © 2021 Bam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


CD4+ helper T (Th) cells play a critical role in shaping anti-tumor immunity by virtue of their ability to differentiate into multiple lineages in response to environmental cues. Various CD4+ lineages can orchestrate a broad range of effector activities during the initiation, expansion, and memory phase of endogenous anti-tumor immune response. In this clinical corelative study, we found that Glioblastoma (GBM) induces multi- and mixed-lineage immune response in the tumor microenvironment. Whole-genome bisulfite sequencing of tumor infiltrating and blood CD4+ T-cell from GBM patients showed 13571 differentially methylated regions and a distinct methylation pattern of methylation of tumor infiltrating CD4+ T-cells with significant inter-patient variability. The methylation changes also resulted in transcriptomic changes with 341 differentially expressed genes in CD4+ tumor infiltrating T-cells compared to blood. Analysis of specific genes involved in CD4+ differentiation and function revealed differential methylation status of TBX21, GATA3, RORC, FOXP3, IL10 and IFNG in tumor CD4+ T-cells. Analysis of lineage specific genes revealed differential methylation and gene expression in tumor CD4+ T-cells. Interestingly, we observed dysregulation of several ligands of T cell function genes in GBM tissue corresponding to the T-cell receptors that were dysregulated in tumor infiltrating CD4+ T-cells. Our results suggest that GBM might induce epigenetic alterations in tumor infiltrating CD4+ T-cells there by influencing anti-tumor immune response by manipulating differentiation and function of tumor infiltrating CD4+ T-cells. Thus, further research is warranted to understand the role of tumor induced epigenetic modification of tumor infiltrating T-cells to develop effective anti-GBM immunotherapy.

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