Glioma Shapes Blood-Brain Barrier Integrity and Remodels the Tumor Microenvironment: Links with Clinical Features and Prognosis.

Abstract

Background: The presence of the blood–brain barrier (BBB) uniquely distinguishes the brain from other organs, and various brain pathologies, including cancer, can disrupt or breach the BBB. The specific implications of BBB alterations in glioma have not been sufficiently clarified. Methods: In this study, statistical analysis of the TCGA pan-glioma dataset and four other validation cohorts was used to investigate the infiltration of BBB constituent cells (endothelial cells, pericytes and astrocytes) in the glioma tumor microenvironment (TME). Results: We found that the infiltration proportions of the three BBB constituent cell types were highly collinear, which implied alteration of the BBB. Hence, we developed an index, the BBB score, which is calculated based on the infiltration proportion of BBB constituent cells. Furthermore, we observed that patients with higher BBB scores were more likely to be diagnosed with more malignant entities in the TCGA database according to significant molecular features, such as IDH mutation status and 1p/19q deletion. The BBB score was also strikingly positively correlated with WHO grade in other cohorts. More importantly, a higher BBB score correlated with shorter survival time and unfavorable prognosis in glioma patients. Finally, we showed that TME-related pathways may regulate BBB alterations and that coinhibitory immune checkpoints were enriched in samples with higher BBB scores. Conclusions: We showed that TME-related pathways may regulate BBB alterations and that coinhibitory immune checkpoints were enriched in samples with higher BBB scores. Assessing BBB alterations may help elucidate the complex role of the glioma TME and suggest new combination treatment strategies.