Immunogenomic Profiling Reveals a Suppressive Tumor Microenvironment and Immune Evasion Signatures In Glioblastoma
About this article
Keywords:
Glioblastoma; Immunogenomics; Immune Evasion; Immune Suppression; Tumor-Infiltrating Immune Cells; Tumor MicroenvironmentAbstract
Glioblastoma (GBM) is an aggressive brain tumor known for its poor prognosis and resistance to immunotherapy, largely due to a pro-foundly immunosuppressive tumor microenvironment. Understanding the immunogenomic landscape of GBM is critical for identifying biomarkers and therapeutic targets. Transcriptomic data from 45 GBM and 8 normal neural stem cell (NSC) samples were analyzed to iden-tify differentially expressed genes (DEGs). Functional enrichment analysis (GO and KEGG), immune cell infiltration scoring (xCell), and immune checkpoint gene profiling were performed to characterize the tumor immune microenvironment. A total of 15,405 DEGs were iden-tified, including 2,044 upregulated and 13,361 downregulated genes. Notably, AGBL5, FDPS, SLC25A3, NONO, ZDHHC16, and NUTF2 were among the most significantly upregulated genes in GBM. GO and KEGG analyses revealed enrichment of cell cycle and ECM remodeling pathways among upregulated genes, and suppression of immune receptor and cytokine signaling pathways among down-regulated genes. Immune profiling showed increased infiltration of immunosuppressive M2 macrophages and reduced NK and dendritic cell presence in GBM. Furthermore, immune checkpoint genes CD274 (PD-L1), CTLA4, and LAG3 were significantly upregulated, indicating a tumor environment favoring immune evasion. These findings reveal that GBM promotes tumor progression and immune evasion through coordinated gene expression changes and cellular reprogramming of the tumor microenvironment. The identified genes and immune signa-tures represent potential candidates for further investigation as biomarkers and therapeutic targets for overcoming GBM-associated immu-nosuppression.
References
[1] Schaff, L. R., & Mellinghoff, I. K. (2023). Glioblastoma and other primary brain malignancies in adults: a review. Jama, 329(7), 574-587. https://doi.org/10.1001/jama.2023.0023.
[2] Eskandar, K. (2024). The evolving role of surgery in multimodal cancer treatment: a comprehensive review. Хирургия и онкология, 14(4), 55-62. https://doi.org/10.17650/2949-5857-2024-14-4-55-62.
[3] Tan, A. C., Ashley, D. M., López, G. Y., Malinzak, M., Friedman, H. S., & Khasraw, M. (2020). Management of glioblastoma: State of the art and future directions. CA: a cancer journal for clinicians, 70(4), 299-312. https://doi.org/10.3322/caac.21613.
[4] Davis, M. E. (2016). Glioblastoma: overview of disease and treatment. Clinical journal of oncology nursing, 20(5), S2. https://doi.org/10.1188/16.CJON.S1.2-8.
[5] Thakkar, J. P., Dolecek, T. A., Horbinski, C. et al. (2014). Epidemiologic and molecular prognostic review of glioblastoma. Cancer epidemiology, biomarkers & prevention, 23(10), 1985-1996. https://doi.org/10.1158/1055-9965.EPI-14-0275.
View more references (19)
[6] Medikonda, R., Dunn, G., Rahman, M., Fecci, P., & Lim, M. (2021). A review of glioblastoma immunotherapy. Journal of Neuro-Oncology, 151(1), 41-53. https://doi.org/10.1007/s11060-020-03448-1.
[7] Haslam A & Prasad V (2019) Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immu-notherapy drugs. JAMA Netw Open 2(5):e192535–e192535. https://doi.org/10.1001/jamanetworkopen.2019.2535.
[8] Robert C, Long GV, Brady B, Dutriaux C, et al. (2015). Nivolumab in previously untreated melanoma without BRAF mutation. New Engl J Med 372(4):320–330. https://doi.org/10.1056/NEJMoa1412082.
[9] Kawengian KJ & Wanandi SI. Evasion of the immune system by glioblastoma multiforme: an obstacle to achieving effective therapies. Mol Cell Bi-omed Sci. 2024;8(2):58–70. https://doi.org/10.21705/mcbs.v8i2.434.
[10] Chen J, Wu Q, Berglund AE, Macaulay RJ & Etame AB. Comprehensive analysis identifies THEMIS2 as a potential prognostic and immunological biomarker in glioblastoma. Cells. 2025;14(2):66. https://doi.org/10.3390/cells14020066.
[11] Xu, D., Cao, M., Wang, B., Bi, X., Zhang, H., Wu, D., ... & Li, K. (2023). Epigenetically regulated lncRNAs dissect the intratumoural heterogeneity and facilitate immune evasion of glioblastomas. Theranostics, 13(5), 1490. https://doi.org/10.7150/thno.79874.
[12] Simonds, E. F., Lu, E. D., Badillo, O. et al. (2021), Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma. Journal for immunotherapy of cancer, 9(6), e002181. https://doi.org/10.1136/jitc-2020-002181.
[13] Su, H., Peng, Y., Wu, Y., & Zeng, X. (2025), Overcoming immune evasion with innovative multi-target approaches for glioblastoma. Frontiers in Immunology, 16, 1541467. https://doi.org/10.3389/fimmu.2025.1541467.
[14] Ricklefs, F. L., Alayo, Q., Krenzlin, H. et al. (2018), Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Science ad-vances, 4(3), eaar2766. https://doi.org/10.1126/sciadv.aar2766.
[15] Gangoso, E., Southgate, B., Bradley, L. et al. (2021), Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell, 184(9), 2454-2470. https://doi.org/10.1016/j.cell.2021.03.023.
[16] GEO Accession viewer. GSE119834. Available from: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119834.
[17] Yuan, Q., Zuo, F. X., Cai, H. Q., Qian, H. P., & Wan, J. H. (2022), Identifying differential expression genes and prognostic signature based on sub-ventricular zone involved glioblastoma. Frontiers in genetics, 13, 912227. https://doi.org/10.3389/fgene.2022.912227.
[18] Mehner, C., Hockla, A., Miller, E., Ran, S., Radisky, D. C., & Radisky, E. S. (2014), Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget, 5(9), 2736. https://doi.org/10.18632/oncotarget.1932.
[19] El Khayari, A., Bouchmaa, N., Taib, B., Wei, Z., Zeng, A., & El Fatimy, R. (2022), Metabolic rewiring in glioblastoma cancer: EGFR, IDH and be-yond. Frontiers in oncology, 12, 901951. https://doi.org/10.3389/fonc.2022.901951.
[20] Dusoswa, S. A., Verhoeff, J., Abels, E. et al. (2020), Glioblastomas exploit truncated O-linked glycans for local and distant immune modulation via the macrophage galactose-type lectin. Proceedings of the National Academy of Sciences, 117(7), 3693-3703. https://doi.org/10.1073/pnas.1907921117.
[21] Guan, X., Wang, Y., Sun, Y. et al. (2021), CTLA4-mediated immunosuppression in glioblastoma is associated with the infiltration of macrophages in the tumor microenvironment. Journal of inflammation research, 7315-7329. https://doi.org/10.2147/JIR.S341981.
[22] Zhang, H., Yang, L., Han, M. et al. (2024), Boost Infiltration and Activity of T Cells via Inhibiting Ecto-5′-nucleotidase (CD73) Immune Checkpoint to Enhance Glioblastoma Immunotherapy. ACS nano, 18(34), 23001-23013. https://doi.org/10.1021/acsnano.4c04553.
[23] Geo. Citing and linking - GEO - NCBI [Internet]. Available from: https://www.ncbi.nlm.nih.gov/geo/info/linking.html.
[24] Saani, I.A.H., Elim, A., Andrew, Z. et al. (2025), Recent discoveries and clinical applications of deoxyribonucleic acid (DNA) methylation inhibitors in the diagnosis, classification, and treatment of meningiomas. biomarkers, 10, 11.