Sexual-biased necroinflammation is revealed as a predictor of bevacizumab benefit in Glioblastoma.

Abstract

Glioblastoma (GBM) is a highly malignant brain tumor that affects men more often than women. In addition, the former shows a poorer survival prognosis. To date the reason for this sex-specific aggressiveness remains unclear. Therefore, the aim of this study is to investigate tumor processes that explain these sex differences. This was a retrospective study of GBM patients which was stratified according to sex. Cohort with 73 tumors were analyzed with immunohistochemistry, RNA-seq and RT-qPCR to characterize differences in vascular and immunological profiles. Transcriptomic profiling, GSEA and pathway enrichment analysis were used for discovery molecular pathways predominant in each group. We further investigated the therapeutic effect of Bevacizumab (VEGFA blocking antibody) in retrospective GBM cohort (36 tumors) based on sex differences. We found that under hypoxic tumor conditions, two distinct tumor immuno-angiogenic ecosystems develop linked to sex differences and ESR1 expression are generated. One of these subgroups, which includes male patients with low ESR1 expression, is characterized by vascular fragility associated with the appearance of regions of necrosis and high inflammation (called necroinflamed tumors). This male-specific tumor subtype shows high inflammation related to MDSC infiltration. Using this stratification, we identified a possible group of patients who could respond to bevacizumab (BVZ) and revealed a genetic signature that may find clinical applications as a predictor of those who may benefit most from this treatment. This study provides a stratification based on the sexual differences in GBM, which associates the poor prognosis with the presence of immunosuppressive myeloid cells in the necrotic areas. This new stratification could change the current prognosis of GBM and identifies those who respond to BVZ treatment.