High p16^INK4A expression in glioblastoma is associated with senescence phenotype and better prognosis

Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (GBM), is the most malignant brain tumor in adults, with limited therapeutic intervention. Previous studies have identified a few prognostic markers for GBM, including the methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter, TERT promoter mutation, EGFR amplification, and CDKN2A/2B deletion. However, the classification of GBM remains incomplete, necessitating a comprehensive analysis. In this study, we investigated the impact of p16^INK4A expression in GBM and found that p16^INK4A-high GBM exhibits distinct characteristics compared to p16^INK4A-low GBM. Specifically, tumor cells with p16^INK4A-high expression display a senescent phenotype and are correlated with higher intra-tumoral immune cell infiltration. Furthermore, an association was observed between elevated p16^INK4A expression in GBM and extended overall survival of patients. Our in vivo and in vitro studies revealed that CCL13 is predominantly expressed by p16^INK4A-high GBM cells. The released CCL13 enhances the infiltration of T cells within the tumor, potentially contributing to the improved prognosis observed in patients with high p16^INK4A expression. These findings suggest that tumor cells with a senescence phenotype in GBM, through the secretion of chemokines such as CCL13, may augment immune cell infiltration and potentially enhance patient outcomes by creating a more immunologically active tumor microenvironment.