Overexpression of key complement regulators in glioblastoma

Abstract

Background: Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor in adults. While immune evasion is a well-recognized driver of GBM progression and a major obstacle for efficient immunotherapy, the role of the complement system remains underexplored. C1-inhibitor (C1-INH), a regulator of complement activation, was recently found overexpressed in GBM. We therefore hypothesized that GBM overexpresses additional complement regulators beyond C1-INH and the present work aimed to identify these.

Method: Gene expression of complement inhibitors, the complement regulator pentraxin-3 (PTX3), and complement proteins was analyzed across nine publicly available transcriptomic datasets. Within each dataset, statistical comparisons were performed between sample groups for each gene. Differentially expressed complement inhibitors were validated at the protein level by immunostaining in the rat GBM cell line NS1 and patient derived GBM tissue.

Results: CFI, encoding factor I, was significantly overexpressed in GBM compared to non-tumoral brain, while THBD and CFH, encoding thrombomodulin and factor H, displayed moderate overexpression. SERPING1, encoding C1-INH, was also upregulated, confirming previous findings. Immunostaining confirmed the expression of these inhibitors in vitro as well as in human glioblastoma tissue. Additionally, PTX3 and early complement proteins were significantly overexpressed in GBM, while levels of C5 and downstream components were comparable to normal brain.

Conclusions: Our findings indicate that the GBM tumor overexpresses a specific set of complement regulators and components of the complement cascade, possibly inhibiting an efficient anti-tumoral immune response. Further investigations of these regulators as potential therapeutical targets in GBM are therefore highly warranted.