O microambiente tumoral de meningiomas: CD73 versus PD-L1 como mecanismos de imunoevasão

Abstract

Meningiomas constitute the most frequent primary tumors of the central nervous system. Although predominantly benign (WHO Grade 1), a significant proportion progresses to atypical (Grade 2) or malignant forms, exhibiting aggressive behavior and high recurrence rates. Current histopathological classification occasionally fails to predict biological behavior, creating a gap in our understanding of the molecular mechanisms governing tumor progression and immune evasion. This study aimed to evaluate the systemic inflammatory profile and the expression of immune and metabolic checkpoints (PD-L1 and CD73) as biomarkers of aggressiveness in a cohort of 40 patients undergoing meningioma resection. Methodology included plasma cytokine quantification (CBA), gene expression analysis (RT-qPCR), and protein validation (immunohistochemistry). Results demonstrated that progression to Grade 2 is not an isolated event, but a systemic one. A trend toward elevated levels of pro-inflammatory (TNF, IFN-γ, IL-1β) and regulatory (IL-10, IL-4) cytokines was observed in the plasma of patients with higher-grade tumors, clinically correlating with a high incidence of seizures (27.5%). Molecularly, a "metabolic switch" was identified in disease progression: while Grade 1 meningiomas presented higher PD-L1 expression (p=0.002), suggesting adaptive immune resistance, Grade 2 meningiomas exhibited significant CD73 overexpression (p=0.037) and a drastic reduction in PD-L1. A negative correlation was found between these markers, indicating that tumor aggressiveness is associated with the transition from classic checkpoint blockade to metabolic immunosuppression mediated by the adenosine pathway. It is concluded that CD73 acts as a pivotal driver of malignancy in meningiomas, simultaneously promoting immune evasion and, potentially, tumor angiogenesis. These findings challenge the efficacy of anti-PD-1 monotherapy for high-grade meningiomas and position CD73 inhibition as a promising and necessary therapeutic strategy for this subgroup of patients.