Glioblastoma Vascular Plasticity Limits Effector T-cell Infiltration and Is Blocked by cAMP Activation

Abstract

Glioblastoma (GBM) is the deadliest form of brain cancer, characterized as a highly angiogenetic and immunosuppressive malignancy. Although immune checkpoint blockades have revolutionized cancer therapy, their therapeutic efficacy in GBM has been far less than expected or even ineffective. Here, we reveal that the genomic signature of glioma-derived endothelial cells (GdECs) correlates with an immunosuppressive state and poor prognosis of glioma patients. In vitro model of GdECs differentiation is established for drug screening, and we identify that cAMP activators could effectively block the GdECs formation by inducing oxidative stress. cAMP activator impairs the GdECs differentiation in vivo, normalizes the tumor vessels, and alters the immune profile, especially increasing the influx and function of CD8+ effector T cells. The dual blockade of GdECs and PD-1 induces tumor regression and establishes anti-tumor immune memory. Our study reveals that endothelial transdifferentiation of GBM shapes an endothelial immune cell barrier and supports the clinical development of combining GdECs blockade and immunotherapy for GBM.

OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

“…Not only too high but also too low oxidative stress may prove critically detrimental in cancer: cyclic adenosine monophosphate (cAMP) activators by inducing oxidative stress impaired glioma-derived endothelial cell differentiation in vivo, normalized the tumor vessels, and altered the tumor immune profile, especially increasing the influx and function of CD8+ effector T-cells [ 139 ].…”