CD80/CD163 macrophage signature identifies high-risk glioblastoma patients

Background & Objectives: Glioblastoma (GBM) is the most common and aggressive glioma in adults, characterized by a highly immunosuppressive tumor immune-microenvironment (TIME). Tumor-associated macrophages (TAMs), which constitute nearly one-third of the TIME, are key regulators of tumor behavior and treatment response. This study investigate the prognostic impact of macrophage polarization in a well-characterized cohort of primary and recurrent GBM patients. Methods: Surgical specimens from 59 adult GBM patients were retrospectively collected, including recurrent tumor tissue when available. Formalin-fixed, paraffin-embedded samples were used to construct tissue microarrays in triplicate, including peritumoral/normal-like and tumor tissue. Clinical data on treatment, recurrence, and survival were gathered. Immunohistochemical expression of CD68, CD80, and CD163 was digitally quantified. Differences between tumor and peritumoral tissues were evaluated using non-parametric tests while survival analyses using Kaplan–Meier curves and log-rank tests. Results: CD68, CD80, and CD163 were significantly upregulated in tumor tissues compared to peritumoral areas in primary GBM (p<0.0002, p=0.0421, and p<0.0001, respectively), whereas in recurrent GBM only CD163 remained significantly elevated (p<0.0024). When comparing primary vs recurrent GBM, a significant decrease in CD68 (p=0.0023) and an increase in CD80 (p=0.0020) were observed in tumor tissue, along with significantly higher CD163 expression in both tumor (p<0.0001) and peritumoral regions (p=0.0078). Patients classified in the CD163High/CD80High subgroup exhibited shorter overall survival (14.2 vs 23.4 months; HR=2.24; 95% CI: 1.2–4.4; p=0.027) and reduced progression-free survival (12.9 vs 15.1 months; HR=1.41; 95% CI: 0.8-2.5; p=0.213) compared to other subgroups. Conclusion: This study highlights the complexity and dynamic architecture of the GBM TIME, driven by multifaceted interactions and cellular plasticity. It challenges the traditional M1/M2 polarization model by revealing synergistic behavior among TAMs subpopulations. In particular, the CD80High/CD163High phenotype emerged as a distinct subset associated with poor prognosis. These findings highlight the prognostic relevance of TAMs polarization and support their potential use as therapeutic targets.