Genome wide DNA methylation landscape reveals glioblastoma’s influence on epigenetic changes in tumor infiltrating CD4+ T cells
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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
Keywords: glioblastoma; malignant glioma; CD4+ T cell; DNA methylation; brain cancer
Received: April 05, 2021 Accepted: April 19, 2021 Published: PUBLISHED_DATE
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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