Macrophage Polarization and Prognostic Implications in Glioblastoma

Introduction: Glioblastoma (GBM) is the most common and aggressive glioma in adults supported by a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), which constitute about one-third of the TME cells, could affect survival and therapeutic response. This study aims to deepen the TAMs prognostic role by analyzing macrophages’ polarization in a well-characterized series of GBM patients. Methods: Surgical specimens of 59 GBM adult patients were retrospectively selected, and where available relapsed tissue was also collected. Adjuvant radio- and chemotherapy, relapse, and cancer-related death times were annotated. Immunohistochemical expression of CD68, CD80, and CD163 was digitally assessed by HALO® v3.6 imaging analysis software. All statistical analyses were performed with SPSS 27.0 and GraphPad Prism v10.1. Results: A total of 23 (39%) patients relapsed and 54 (92%) died during the follow-up. Biomarker analysis showed higher levels of CD68 (p<0.00019), CD80 (p=0.0421) and CD163 (p<0.0001) in GMB tissues compared to peritumoral tissues, with significant CD163 upregulation (p<0.0024) in recurrent tumors tissue. CD163 were significantly higher in peritumoral (p=0.0078) and GMB tissue (p<0.0001) in relapses vs primary GBM. Spearman analysis supported positive correlation among these markers in primary and recurrent tissues. Prognostically, CD163High/CD80High subgroup showed a lower overall survival (OS), (HR=2.24; 95% CI: 1.2-4.4; p=0.027) and progression-free survival (PFS), (HR=1.41; 95%CI: 0.8-2.5; p=0.213) compared to other subgroups. Conclusion: This study confirms the intricacy and multifaceted GBM’s microenvironment. It challenges the notion of macrophage polarization as a simple M1 or M2 dichotomy, despite the notable CD163 expression in GBM TME. Instead, it suggests a synergy between macrophage populations, by identifying a subgroup with high concurrent CD80 and CD163 expression as a negative prognostic factor for OS and PFS. These findings highlight TAMs as potential therapeutic targets and may lead to personalized oncology therapies.