These oncotarget results suggest that GBM could induce epigenetic changes in tumor-infiltrating CD4 T cells

Oncotarget released “Genome-wide DNA methylation landscape shows the influence of glioblastoma on epigenetic changes in tumor-infiltrating CD4 + T cells“Who reported that bisulfite sequencing of the entire genome of tumor infiltrating and blood CD4 T cells from GBM patients 13571 differently methylated regions and a pronounced methylation pattern of methylation of tumor infiltrating CD4 T cells with significant variability between patients exhibited.

The methylation changes also led to transcriptomic changes with 341 differently expressed genes in CD4 tumor-infiltrating T cells compared to blood.

Analysis of specific genes involved in CD4 differentiation and function revealed different methylation status of TBX21, GATA3, RORC, FOXP3, IL10 and IFNG in tumor CD4 T cells.

Interestingly, the authors observed a dysregulation of several ligands of T cell functional genes in GBM tissue, which correspond to the T cell receptors that were dysregulated in tumor-infiltrating CD4 T cells.

These oncotarget results suggest that GBM could induce epigenetic changes in tumor-infiltrating CD4 T cells there by influencing the anti-tumor immune response by manipulating the differentiation and function of tumor-infiltrating CD4 T cells.

These oncotarget results suggest that GBM could induce epigenetic changes in tumor-infiltrating CD4 T cells

Dr. Mahua Dey of the University of Wisconsin-Madison and Indiana University School of Medicine said: “The naive CD4 + helper T cell population is known for its polyfunctionality and highly plastic properties.

In the tumor microenvironment, the lineage obligations of CD4 T cells reflect the initiation of new gene expression programs in tumor-infiltrating naive T cells.

The microenvironment of the GBM tumor is known to be extremely immunosuppressive and has several unique properties, including:

  1. Impaired cellular immunity, not a lack of tumor-infiltrating T cells
  2. High levels of TGFβ secreted by both resident and circulating microglia and
  3. Expression of several inhibitory ligands that trigger anergy and apoptosis of cytotoxic lymphocytes in the TME, immune checkpoint expression and increased infiltration of immunosuppressive cells.

Genome-wide methylation sequencing revealed 13571 uniquely differentially methylated regions, mainly concentrated around the TSS, in the CD4 T cells of GBM patient tumors compared to blood.

In addition, by combining transcriptomic data from RNAseq analysis with DNA methylation, we observed differential methylation of gene sets specific for CD4 T cells, including Th1, Th2, Th17 and iTregs in GBM tumors, albeit with significant inter-patient variability.

In summary, these data show for the first time unique DNA methylation patterns and gene expression profiles in GBM-associated tumor-infiltrating CD4 T cells compared to CD4 T cells from the blood of the same patient and some of their ligands on the GBM cells, suggesting: that the function and differentiation of CD4 T cells by the GBM-TME can be influenced by epigenetic mechanisms such as DNA methylation.

The Dey research team concluded in their oncotarget research result: “In the present clinical report, we have shown that a different DNA methylation pattern could influence gene expression in tumor-infiltrating CD4 + T cells compared to circulating CD4 + T cells in the blood in GBM patients. Our results show that GBM may affect the condition of tumor-infiltrating CD4 + T cells through epigenetic modification in the form of DNA methylation of important genes that regulate immune function and affect the fate of helper T cells in GBM-TME. Based on our observations, we believe that the epigenetic interaction between GBM and tumor-infiltrating CD4 + T cells may be responsible for the immunocompromised state of GBM patients. Our data convincingly show that there is a significant inter-patient variability in GBM tumor ligand expression of different T-cell-modulating ligands and consequently striking differences in methylation pattern and gene expression in tumor-infiltrating CD4 + T-cells. This has a very strong bearing on the selection of future patients for immunotherapy trials who, due to their tumor immuno-signature, have a higher probability of responding to immunotherapy than others. The results of our correlative study need to be further validated in the experimental setting.

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DOI – https: //doi.Organization/10.18632 /onkoziel.27955

Full text – https: //www.onkoziel.com /Items/27955 /Text/

Correspondence – Mahua Dey – [email protected]

keywords
Glioblastoma,
malignant glioma,
CD4 + T cell,
DNA methylation,
Brain tumor

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