Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

Tompa, Márton; Kraboth, Zoltan; Gálik, Bence; Kajtár, Béla; Gyenesei, Attila; Kálmán, Bernadette

doi:10.3390/biomedicines10092174

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…[ 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.…”

Section: Immune Checkpoint Inhibitors In Glioblastomamentioning

confidence: 99%

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

Ser,

Webb,

Sener

et al. 2024

Journal of Immunotherapy and Precision Oncology

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Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

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Section: Immune Checkpoint Inhibitors In Glioblastomamentioning

confidence: 99%

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

Ser,

Webb,

Sener

et al. 2024

Journal of Immunotherapy and Precision Oncology

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“…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.…”

Section: Targetmentioning

confidence: 99%

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

Lin,

Liu,

et al. 2024

J Hematol Oncol

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Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4–8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.

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