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

Abstract

Background: 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. Methods: 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 IL-6 expression. The Tumor IMmune Estimation Resource database was used to analyze the association between IL-6 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. Results: Bioinformatics analysis revealed that high IL-6 expression is associated with the activation of procancer pathways, that there is a positive correlation between IL-6 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. Conclusion: Elevated IL-6 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.