Elevated Serum IL-6 As a Negative Prognostic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Validation

Overview

Journal J Cancer

Date 2025 Jan 9

PMID 39781345

Authors

Sup Kim

Kyung Hwan Kim

Hee-Won Jung

Eun-Oh Jeong

Han-Joo Lee

Jeanny Kwon

Hyon-Jo Kwon

Seung-Won Choi

Hyeon-Song Koh

Seon-Hwan Kim

Affiliations

Soon will be listed here.

Abstract

Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, necessitating the discovery of reliable serum prognostic biomarkers. This study aimed to investigate the prognostic value of serum Interleukin-6 (IL-6) in GBM patients. Bioinformatics analysis via gene set enrichment analysis was conducted on The Cancer Genome Atlas RNA-seq data to explore the pathways enriched in samples with high expression. The Tumor IMmune Estimation Resource database was used to analyze the association between expression and immune cell infiltration. To validate the role of IL-6 in a clinical setting, a retrospective cohort study was conducted on newly diagnosed GBM patients. Serum IL-6 levels were repeatedly measured at key milestone time points, and their correlation with survival data was analyzed. Bioinformatics analysis revealed that high expression is associated with the activation of procancer pathways, that there is a positive correlation between expression and immune cell infiltration in GBM. Between March 2021 and September 2023, 36 GBM patients and their serum IL-6 measurements at various time points were included in the clinical data analyses. Elevated serum IL-6 levels at baseline, with a cutoff of 7pg/mL, were identified in 11 patients (30.6%). In the multivariate analyses for overall survival (OS), elevated IL-6 was a significant risk factor (p = 0.048), along with unfavorable surgical resection (p = 0.039) and O6-methylguanine-DNA methyltransferase promotor unmethylation (p = 0.027). The median actuarial OS of the high initial IL-6 group was significantly shorter than that of the low initial IL-6 group (6.4 vs. 19.7 months, p < 0.001). However, IL-6 levels at other time points were not related to patient prognosis. Elevated mRNA expression is correlated with the activation of procancer pathways, increased immune cell infiltration, and poor prognosis in GBM patients. In addition, elevated serum IL-6 at baseline is a negative prognostic factor confirmed in a clinical study. Serum IL-6 may be a potential prognostic biomarker enhancing the management of GBM.

References

Reynes G, Vila V, Martin M, Parada A, Fleitas T, Reganon E . Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma. J Neurooncol. 2010; 102(1):35-41. DOI: 10.1007/s11060-010-0290-x. View

Batchelor T, Duda D, Tomaso E, Ancukiewicz M, Plotkin S, Gerstner E . Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010; 28(17):2817-23. PMC: 2903316. DOI: 10.1200/JCO.2009.26.3988. View

Huang X, Liu S, Wu L, Jiang M, Hou Y . High Throughput Single Cell RNA Sequencing, Bioinformatics Analysis and Applications. Adv Exp Med Biol. 2018; 1068:33-43. DOI: 10.1007/978-981-13-0502-3_4. View

West A, Tsui V, Stylli S, Nguyen H, Morokoff A, Kaye A . The role of interleukin-6-STAT3 signalling in glioblastoma. Oncol Lett. 2018; 16(4):4095-4104. PMC: 6144698. DOI: 10.3892/ol.2018.9227. View

Louis D, Ohgaki H, Wiestler O, Cavenee W, Burger P, Jouvet A . The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007; 114(2):97-109. PMC: 1929165. DOI: 10.1007/s00401-007-0243-4. View

Chen X, Zhou J, Chen C, Hou B, Ali A, Li F . Consecutive Monitoring of Interleukin-6 Is Needed for COVID-19 Patients. Virol Sin. 2021; 36(5):1093-1096. PMC: 8261036. DOI: 10.1007/s12250-021-00425-4. View

Bizon M, Awizen-Panufnik Z, Sawicki W . Comparison of Interleukin-6 with Other Markers in Diagnosis of Ovarian Cancer. J Pers Med. 2023; 13(6). PMC: 10301870. DOI: 10.3390/jpm13060980. View

van Meir E, Sawamura Y, Diserens A, Hamou M, Tribolet N . Human glioblastoma cells release interleukin 6 in vivo and in vitro. Cancer Res. 1990; 50(20):6683-8. View

Szopa W, Burley T, Kramer-Marek G, Kaspera W . Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives. Biomed Res Int. 2017; 2017:8013575. PMC: 5337853. DOI: 10.1155/2017/8013575. View

10.

Castro F, Cardoso A, Goncalves R, Serre K, Oliveira M . Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front Immunol. 2018; 9:847. PMC: 5945880. DOI: 10.3389/fimmu.2018.00847. View

11.

Taki M, Abiko K, Ukita M, Murakami R, Yamanoi K, Yamaguchi K . Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition. Clin Cancer Res. 2021; 27(17):4669-4679. DOI: 10.1158/1078-0432.CCR-20-4459. View

12.

Bunevicius A, Radziunas A, Tamasauskas S, Tamasauskas A, Laws E, Iervasi G . Prognostic role of high sensitivity C-reactive protein and interleukin-6 in glioma and meningioma patients. J Neurooncol. 2018; 138(2):351-358. DOI: 10.1007/s11060-018-2803-y. View

13.

Wang Q, He Z, Huang M, Liu T, Wang Y, Xu H . Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α. Nat Commun. 2018; 9(1):559. PMC: 5805734. DOI: 10.1038/s41467-018-03050-0. View

14.

Shan Y, He X, Song W, Han D, Niu J, Wang J . Role of IL-6 in the invasiveness and prognosis of glioma. Int J Clin Exp Med. 2015; 8(6):9114-20. PMC: 4538008. View

15.

Inda M, Bonavia R, Mukasa A, Narita Y, Sah D, Vandenberg S . Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev. 2010; 24(16):1731-45. PMC: 2922502. DOI: 10.1101/gad.1890510. View

16.

Tchirkov A, Khalil T, Chautard E, Mokhtari K, Veronese L, Irthum B . Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br J Cancer. 2007; 96(3):474-6. PMC: 2360031. DOI: 10.1038/sj.bjc.6603586. View

17.

Tchirkov A, Rolhion C, Bertrand S, Dore J, Dubost J, Verrelle P . IL-6 gene amplification and expression in human glioblastomas. Br J Cancer. 2001; 85(4):518-22. PMC: 2364101. DOI: 10.1054/bjoc.2001.1942. View

18.

Affronti M, Heery C, Herndon 2nd J, Rich J, Reardon D, Desjardins A . Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer. 2009; 115(15):3501-11. DOI: 10.1002/cncr.24398. View

19.

Nagy A, Munkacsy G, Gyorffy B . Pancancer survival analysis of cancer hallmark genes. Sci Rep. 2021; 11(1):6047. PMC: 7961001. DOI: 10.1038/s41598-021-84787-5. View

20.

Ashizawa T, Okada R, Suzuki Y, Takagi M, Yamazaki T, Sumi T . Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor. Gastric Cancer. 2005; 8(2):124-31. DOI: 10.1007/s10120-005-0315-x. View