Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

Abstract

Background: Immune evasion in glioblastoma (GBM) shields cancer cells from cytotoxic immune response. Methods: We investigated CpG methylation in promoters, genes, and pathways in 22 pairs of formalin-fixed paraffin-embedded sequential (FFPE) GBM using restricted resolution bisulfite sequencing (RRBS) and bioinformatic analyses. Results: Gene ontology revealed hypermethylation in elements of the innate and adaptive immune system when recurrent GBM samples (GBMrec) were compared to control (CG) and primary GBM samples (GBMprim). Higher methylation levels of the IL-7 signaling pathway and response to IL-7 were found in GBMrec suggesting a progressive blockade of the IL-7 driven T cell response in sequential GBM. Analyses of the Cancer Genome Atlas array-based data confirmed hypermethylation of the IL-7 pathway in recurrent compared with primary GBM. We also quantified DNA CpG methylation in promoter and gene regions of the IL-7 ligand and IL-7 α-receptor subunit in individual samples of a large RRBS-based sequential cohort of GBM in a Viennese database and found significantly higher methylation levels in the IL-7 receptor α-subunit in GBMrec compared with GBMprim. Conclusions: This study revealed the progressive suppression of the IL-7 receptor-mediated pathway as a means of immune evasion by GBM and thereby highlighted it as a new treatment target.

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions

“…[ 111 ] The progressive suppression of the IL-7 receptor-mediated pathway is related to immune evasion in GBM. [ 112 ] Efineptakin alpha, a long-acting recombinant human IL-7, was demonstrated to be associated with increased survival in combination with RT and TMZ in a mouse glioma model. [ 113 ] This survival benefit was related to the reversal of iatrogenic lymphopenia induced by RT and TMZ because of IL-7–driven lymphocyte expansion, increased cytotoxic CD8 T cells, and decreased Tregs in the TME.…”

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

“…Modifying in epigenetic Impact on the immune microenvironment of GBM Reference IRF8 DNA Methylation Promote immune evasion and transformation of GBM into mesenchymal types [49] OLFML3 CLOCK mediated transcriptional upregulation Promote self-renewal of GSC and recruit TMAs [50] YY1 m6A modifying Promote Treg infiltration [51] KDM4A Demethylation of H3K9me3 Inhibit cell autophage [52] KDM6A Demethylation of H3K27me3 Promote CD8 + T cell exhaustion [54] KDM6B Demethylation of H3K27me3 Promote the immunosuppressive function of myeloid cells [63] IDH DNA Methylation Suppress CD3 + & CD8 + T cell infiltration [66] IFN-α BET & HDAC modifying Regulate the expression of ISG and PD-L1 [68] BRD4 Promote H3K27ac modifying Maintain immunosuppressive microenvironment [69] ALKBH5 m6A demethylation Recruite TAM [70] Integrin β1 Increased chromatin accessibility Recruite MDSC [71] EZH2 Promote H3K27me3 in the promoter of iNOS and TNFα Promote the formation of M2 type macrophage [72] IGFBP1 m6A modifying Sustain immunosuppressive microenvironment [73] IL-7 Methylation Promote immune evasion [74] CXCL9/10 H3K27me3 Suppress T cell recruitment [75] GPX7 DNA Methylation Inhibit innate immunity and adaptive immunity [76] MTAP DNA Methylation Suppress macrophage recruitment [77] MIR155HG Reduce methylation levels in promoter Suppress immunocell infiltration [78] FOXP3 Demethylation Affect the generation of Treg and CD4 + T cell [79,80] LSD1 Histone demethylase Inhibit p53 pathway [81] JMJD3 Histone demethylase Inhibit p53 pathway [82] KAT8 H4K16ac Promote the production of tumor-associated microglia [83] H3.3 G34R/V Regulate the cGAS/STING pathway [84] Lin et al Journal of Hematology & Oncology (2024) 17:31 and CD45RO + [87]. Through techniques such as spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq), it becomes evident that GBM cells could induce local environmental changes through signaling and structural alterations.…”